rs764789036

Variant names:

• chrX-71141265-GCAGCAA-G
• rs764789036
• NM_005120.3:c.6315_6320delACAGCA

Your query was ambiguous. Multiple possible variants found:

• chrX-71141265-GCAGCAA-G
• chrX-71141265-GCAGCAA-GCAGCAACAGCAA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_005120.3(MED12):​c.6315_6320delACAGCA​(p.Gln2106_Gln2107del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,159,273 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q2105Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 52 hem.)
• Consequence: MED12 NM_005120.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.50
• Publications: 1 publications found

Genes affected

MED12 (HGNC:11957): (mediator complex subunit 12) The initiation of transcription is controlled in part by a large protein assembly known as the preinitiation complex. A component of this preinitiation complex is a 1.2 MDa protein aggregate called Mediator. This Mediator component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates. The MED12 protein is essential for activating CDK8 kinase. Defects in this gene cause X-linked Opitz-Kaveggia syndrome, also known as FG syndrome, and Lujan-Fryns syndrome. [provided by RefSeq, Aug 2009]

MED12 Gene-Disease associations (from GenCC):

• FG syndrome 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• MED12-related intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3
• BP6: Variant X-71141265-GCAGCAA-G is Benign according to our data. Variant chrX-71141265-GCAGCAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 458830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000202 (22/108870) while in subpopulation NFE AF = 0.000402 (21/52274). AF 95% confidence interval is 0.000268. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.6315_6320delACAGCA	p.Gln2106_Gln2107del	disruptive_inframe_deletion	Exon 43 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.6315_6320delACAGCA	p.Gln2106_Gln2107del	disruptive_inframe_deletion	Exon 43 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.000202 AC: 22 AN: 108870 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000984

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000402

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000106 AC: 12 AN: 113583 AF XY: 0.0000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 166 AN: 1050403 Hom.: 0 AF XY: 0.000152 AC XY: 52 AN XY: 341557

African (AFR) AF: 0.0000402 AC: 1 AN: 24850

American (AMR) AF: 0.000179 AC: 5 AN: 27909

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18616

East Asian (EAS) AF: 0.00 AC: 0 AN: 27122

South Asian (SAS) AF: 0.00 AC: 0 AN: 49773

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37626

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4041

European-Non Finnish (NFE) AF: 0.000174 AC: 142 AN: 816218

Other (OTH) AF: 0.000384 AC: 17 AN: 44248

GnomAD4 genome AF: 0.000202 AC: 22 AN: 108870 Hom.: 0 Cov.: 23 AF XY: 0.000190 AC XY: 6 AN XY: 31608

African (AFR) AF: 0.00 AC: 0 AN: 29801

American (AMR) AF: 0.0000984 AC: 1 AN: 10159

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2614

East Asian (EAS) AF: 0.00 AC: 0 AN: 3432

South Asian (SAS) AF: 0.00 AC: 0 AN: 2535

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.000402 AC: 21 AN: 52274

Other (OTH) AF: 0.00 AC: 0 AN: 1452

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 29, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MED12: BS2 -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 17, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FG syndrome Benign:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=187/13	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs764789036; hg19: chrX-70361115; COSMIC: COSV105882335;