rs28940309
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_015335.5(MED13L):āc.752A>Gā(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 (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000075 ( 0 hom. )
Consequence
MED13L
NM_015335.5 missense
NM_015335.5 missense
Scores
1
9
9
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MED13L. . Gene score misZ 3.691 (greater than the threshold 3.09). Trascript score misZ 6.2821 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, congenital heart disease, cardiac anomalies - developmental delay - facial dysmorphism syndrome.
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 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251226Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135776
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461706Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727154
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Transposition of the great arteries, dextro-looped Uncertain:2
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
A
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.
REVEL
Uncertain
Sift
Benign
D;.;.;.
Sift4G
Uncertain
D;.;.;.
Polyphen
P;.;.;.
Vest4
MutPred
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at