rs28940309

chr12-116019846-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_015335.5(MED13L):c.752A>G(p.Glu251Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MED13L NM_015335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 5.93

Genes affected

MED13L (HGNC:22962): (mediator complex subunit 13L) The protein encoded by this gene is a subunit of the Mediator complex, a large complex of proteins that functions as a transcriptional coactivator for most RNA polymerase II-transcribed genes. The encoded protein is involved in early development of the heart and brain. Defects in this gene are a cause of transposition of the great arteries, dextro-looped (DTGA).[provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MED13L

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED13L	NM_015335.5	c.752A>G	p.Glu251Gly	missense_variant	6/31	ENST00000281928.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED13L	ENST00000281928.9	c.752A>G	p.Glu251Gly	missense_variant	6/31	1	NM_015335.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251226 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000307 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Transposition of the great arteries, dextro-looped Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 08, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 251 of the MED13L protein (p.Glu251Gly). This variant is present in population databases (rs28940309, gnomAD 0.0009%). This missense change has been observed in individual(s) with transposition of the great arteries (PMID: 14638541). ClinVar contains an entry for this variant (Variation ID: 2106). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MED13L protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Impaired intellectual development and distinctive facial features with cardiac defects Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 09, 2003

- -

Cardiac anomalies - developmental delay - facial dysmorphism syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0107 - This gene is known to be associated with autosomal dominant disease. 0112 - Variants in this gene are known to have reduced penetrance (PMID: 14638541). 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. 0301 - Variant is absent from gnomAD. 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. 0600 - Variant is located in an annotated domain or motif that does not have a well established function. 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - Variant has not previously been reported in a clinical context. 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.7	N;.;.;.
REVEL	Uncertain	0.59
Sift	Benign	0.030	D;.;.;.
Sift4G	Uncertain	0.022	D;.;.;.
Polyphen		0.77	P;.;.;.
Vest4		0.79
MutPred		0.63		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;.;
MVP		0.79
MPC		0.17
ClinPred		0.82	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28940309; hg19: chr12-116457651;