17-61946535-C-T

Variant names:

• chr17-61946535-C-T
• NM_005121.3:c.6458G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005121.3(MED13):​c.6458G>A​(p.Arg2153His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2153C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MED13 NM_005121.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED13	NM_005121.3	c.6458G>A	p.Arg2153His	missense_variant	Exon 30 of 30	ENST00000397786.7	NP_005112.2
MED13	XM_011525551.3	c.6299G>A	p.Arg2100His	missense_variant	Exon 29 of 29		XP_011523853.1
MED13	XM_011525553.4	c.5789G>A	p.Arg1930His	missense_variant	Exon 27 of 27		XP_011523855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED13	ENST00000397786.7	c.6458G>A	p.Arg2153His	missense_variant	Exon 30 of 30	1	NM_005121.3	ENSP00000380888.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461560 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727096

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MED13: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.54
Sift	Benign	0.085	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.29		Loss of stability (P = 0.1211);
MVP		0.68
MPC		2.2
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.66

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: chr17-60023896;