chr17-61946530-A-T

Position:

• chr17-61946530-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_005121.3(MED13):​c.6463T>A​(p.Cys2155Ser) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED13 NM_005121.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.85

Genes affected

MED13 (HGNC:22474): (mediator complex subunit 13) This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional coactivator complex thought to be required for the expression of almost all genes. The mediator complex is recruited by transcriptional activators or nuclear receptors to induce gene expression, possibly by interacting with RNA polymerase II and promoting the formation of a transcriptional pre-initiation complex. The product of this gene is proposed to form a sub-complex with MED12, cyclin C, and CDK8 that can negatively regulate transactivation by mediator. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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), MED13. . Gene score misZ 2.6232 (greater than the threshold 3.09). Trascript score misZ 3.3083 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, intellectual developmental disorder 61, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED13	NM_005121.3	c.6463T>A	p.Cys2155Ser	missense_variant	30/30	ENST00000397786.7
MED13	XM_011525551.3	c.6304T>A	p.Cys2102Ser	missense_variant	29/29
MED13	XM_011525553.4	c.5794T>A	p.Cys1932Ser	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED13	ENST00000397786.7	c.6463T>A	p.Cys2155Ser	missense_variant	30/30	1	NM_005121.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.6463T>A (p.C2155S) alteration is located in exon 30 (coding exon 30) of the MED13 gene. This alteration results from a T to A substitution at nucleotide position 6463, causing the cysteine (C) at amino acid position 2155 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.75		Gain of disorder (P = 7e-04);
MVP		0.90
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-60023891;