rs1057520056

chr12-115997209-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_015335.5(MED13L):c.2591T>A(p.Met864Lys) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M864L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MED13L NM_015335.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.72

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 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015335.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-115997210-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265523.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, MED13L
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant 12-115997209-A-T is Pathogenic according to our data. Variant chr12-115997209-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376790.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED13L	NM_015335.5	c.2591T>A	p.Met864Lys	missense_variant	15/31	ENST00000281928.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED13L	ENST00000281928.9	c.2591T>A	p.Met864Lys	missense_variant	15/31	1	NM_015335.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jul 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0080	D;.;.
Polyphen		0.97	D;.;.
Vest4		0.95
MutPred		0.50		Gain of catalytic residue at P868 (P = 8e-04);Gain of catalytic residue at P868 (P = 8e-04);.;
MVP		0.92
MPC		0.94
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.96

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: rs1057520056; hg19: chr12-116435014;