Variant classification summary

NM_003467.3:c.1013C>G

CXCR4 · NP_003458.1:p.(Ser338Ter) · NM_003467.3

GRCh37: chr2:136872485 G>C · GRCh38: chr2:136114915 G>C

Gene: CXCR4 Transcript: NM_003467.3

Final call

Pathogenic

PS3 strong PS4 strong PM2 supporting PP1 supporting

Variant details

Gene

CXCR4

Transcript

NM_003467.3

Protein

NP_003458.1:p.(Ser338Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong exact-variant assays showed abnormal CXCR4 signaling and disease-relevant phenotypes.

2

Pathogenic: PS4 strong showed 37/131 cases versus 0/32 controls, with corrected OR 26.07 and a confidence interval excluding 1.

3

Pathogenic: PM2 supporting reflects the variant's absence from the queried gnomAD datasets.

4

Pathogenic: PP1 supporting reflects multiple affected family members carrying the exact variant.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule, with PM2 and PP1 providing additional supporting evidence.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	Not met: p.Ser338Ter removes only the final 15 residues and preserves enhanced CXCR4 signaling, demonstrating gain of function rather than the required loss-of-function mechanism.	PMID:15536153 PMID:18436740 PMID:23009155 pvs1_generic_framework
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PS2	Not met	Not met: the exact variant was reported in affected siblings inherited from their father and in three patients from one pedigree, demonstrating familial rather than de novo transmission.	PMID:15536153 PMID:23009155
PS3	Met	Met, strong: exact-variant patient and model assays showed impaired CXCR4 desensitization, enhanced chemotaxis/signaling, and increased tumor dissemination in SCID/Bg mice.	PMID:15536153 PMID:18436740 PMID:24711662
PS4	Met	Met: exact-variant enrichment was 37/131 cases versus 0/32 healthy controls, yielding corrected OR 26.07 and 95% CI 1.56-436.79, above the OR >5.0 threshold.	PMID:24711662 PMID:18436740 PMID:15536153 PMID:23009155
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, meeting the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the reported CXCR4 disease mechanism is autosomal dominant, whereas PM3 requires a pathogenic variant in trans for a recessive disorder.	PMID:15536153 PMID:23009155 PMID:25741868
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a nonsense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PM6	Not met	Not met: the exact variant was reported as inherited from the father in affected siblings and in three patients from one pedigree, not as assumed de novo.	PMID:15536153 PMID:23009155
PP1	Met	Met at supporting strength: affected siblings and three patients from one pedigree carried the exact variant, providing multiple affected relatives with concordant familial transmission.	PMID:15536153 PMID:23009155
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: NM_003467.3:c.1013C>G is a nonsense variant, outside PP3's missense or splice-region/intronic scope.
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not supplied, so phenotype specificity for WHIM cannot be judged.	PMID:15536153 PMID:18436740 PMID:23009155
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel submission, only laboratory or non-expert Pathogenic assertions.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 threshold of 5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: no gnomAD filtering allele frequency is reported because the variant is absent, below the generic BS1 default of 1%.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carries the variant in the relevant zygosity required for BS2.
BS3	Not met	Not met: exact-variant studies showed abnormal CXCR4 trafficking, signaling, chemotaxis, and tumor phenotypes rather than preserved function or normal splicing.	PMID:15536153 PMID:18436740 PMID:24711662
BS4	Not assessed	Not assessed: reports show affected carriers but provide no documented affected non-carrier or other lack-of-segregation observation.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a nonsense variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phased pathogenic allele in cis or trans is documented, and full penetrance of the dominant disorder is not established.	PMID:15536153 PMID:18436740 PMID:23009155 PMID:25741868
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a nonsense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: NM_003467.3:c.1013C>G is a nonsense variant, outside BP4's missense or splice-region/intronic scope.
BP5	Not assessed	Not assessed: no case-specific evidence shows an alternate molecular basis for the disease alongside this variant.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification is present.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a nonsense variant.	generic_acmg_combination_rules

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