rs1555246154

Positions:

• chr12-115997221-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_015335.5(MED13L):​c.2579A>G​(p.Asp860Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED13L NM_015335.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.48

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 12-115997221-T-C is Pathogenic according to our data. Variant chr12-115997221-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-115997221-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED13L	NM_015335.5	c.2579A>G	p.Asp860Gly	missense_variant	15/31	ENST00000281928.9	NP_056150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED13L	ENST00000281928.9	c.2579A>G	p.Asp860Gly	missense_variant	15/31	1	NM_015335.5	ENSP00000281928	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics, University of Zurich

May 18, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2022

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28645799, 24896178, 29951696, 29593475) -

Transposition of the great arteries, dextro-looped Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 860 of the MED13L protein (p.Asp860Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with syndromic intellectual disability (PMID: 24896178, 28645799). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 427897). 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 expected to disrupt MED13L protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.3	D;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0070	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.49
MutPred		0.43		Gain of catalytic residue at P855 (P = 8e-04);Gain of catalytic residue at P855 (P = 8e-04);.;
MVP		0.69
MPC		0.80
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555246154; hg19: chr12-116435026;