NM_005120.3:c.131G>A

MED12 · NP_005111.2:p.(Gly44Asp) · NM_005120.3

GRCh37: chrX:70339254 G>A · GRCh38: chrX:71119404 G>A

Gene: MED12 Transcript: NM_005120.3

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting

Variant details

Gene

MED12

Transcript

NM_005120.3

Protein

NP_005111.2:p.(Gly44Asp)

gnomAD AF

ClinVar

other

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

Likely Pathogenic: PS3 strong—exact p.Gly44Asp disrupted MED12 kinase-module binding and altered cellular signaling.

Likely Pathogenic: PM1 moderate—codon 44 is a recurrent MED12 mutational hotspot without observed benign variation.

Likely Pathogenic: PM2 supporting—the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Generic ACMG/AMP 2015 rules support Likely Pathogenic for one strong pathogenic criterion plus one moderate and one supporting pathogenic criterion, with no benign rule satisfied.

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	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: p.Gly44Asp is reported, but no supplied source establishes that same amino-acid change as pathogenic.	clinvar PMID:26018969 PMID:28771672
PS2	Not assessed	Not assessed: no evidence documents a germline de novo variant with both maternity and paternity confirmed in an affected proband.
PS3	Met	Met, strong: exact p.Gly44Asp showed reproducibly reduced Cyclin C/CDK8/CDK19 binding (AP-MS n=3) and independent cellular signaling abnormalities versus wild type.	PMID:24746821 PMID:32046450
PS4	Not met	Not met: available studies report somatic cases but no variant-specific affected-versus-control comparison, so no PS4 odds ratio and confidence interval can be calculated.	PMID:26822237 PMID:26018969 PMID:28771672
PM1	Met	Met: codon 44 contains 74% of reported MED12 mutations and is a statistically significant hotspot, with the variant absent from gnomAD v2.1 and v4.1.	hotspots PMID:26018969 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, consistent with frequency <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no second pathogenic MED12 variant with confirmed trans phase is documented in an affected germline proband.	PMID:26018969 PMID:28771672 PMID:32046450
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: available reports show the same p.Gly44Asp change, but no different pathogenic missense change at residue 44.	PMID:26018969 PMID:28771672 clinvar
PM6	Not assessed	Not assessed: no clinical report supports an assumed de novo occurrence without parental maternity and paternity confirmation.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are reported to demonstrate cosegregation of the variant with disease.
PP2	Not assessed	Not assessed: the supplied evidence lacks both a gene-wide low-benign-missense metric and a qualifying common missense disease-mechanism demonstration.
PP3	Not met	Not met: this missense variant requires REVEL, but no REVEL score is available; SpliceAI and BayesDel cannot substitute for the applicable predictor path.
PP4	Not assessed	Not assessed: no patient phenotype or family-history description is available to evaluate specificity for a single-gene disease.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification; the record is labeled other with no assertion criteria.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the >=5% BA1 frequency threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from all reported gnomAD datasets, providing no allele frequency above the generic >=1% BS1 default.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier or hemizygote observation is documented for this variant.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: exact p.Gly44Asp reduced MED12-associated CDK8/19 activity and altered cellular signaling rather than showing no damaging effect.	PMID:24746821 PMID:32046450
BS4	Not assessed	Not assessed: no affected relatives without the variant or other family testing data are reported to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the supplied materials do not establish that MED12 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no pathogenic MED12 variant in confirmed trans or cis phase is documented in a qualifying germline observation.	PMID:26018969 PMID:28771672 PMID:32046450
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: this missense variant requires REVEL, but no REVEL score is available; SpliceAI and BayesDel cannot substitute for the applicable predictor path.
BP5	Not met	Not met: no disease case is documented with an established alternate molecular basis; somatic tumor reports alone do not satisfy BP5.	PMID:26018969 PMID:28771672 PMID:32046450
BP6	Not met	Not met: ClinVar provides no exact-variant expert-panel benign or likely benign classification, only an other label without assertion criteria.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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