17-61952972-G-A

Position:

• chr17-61952972-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005121.3(MED13):​c.6110C>T​(p.Ala2037Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,282 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (57 hom.)
• Consequence: MED13 NM_005121.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64

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 Benign. Variant got -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.002184242).
• BP6: Variant 17-61952972-G-A is Benign according to our data. Variant chr17-61952972-G-A is described in ClinVar as [Benign]. Clinvar id is 777207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1940/152170) while in subpopulation AFR AF= 0.0442 (1835/41496). AF 95% confidence interval is 0.0425. There are 40 homozygotes in gnomad4. There are 911 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1940 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED13	NM_005121.3	c.6110C>T	p.Ala2037Val	missense_variant	27/30	ENST00000397786.7
MED13	XM_011525551.3	c.5951C>T	p.Ala1984Val	missense_variant	26/29
MED13	XM_011525553.4	c.5441C>T	p.Ala1814Val	missense_variant	24/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED13	ENST00000397786.7	c.6110C>T	p.Ala2037Val	missense_variant	27/30	1	NM_005121.3	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1938 AN: 152052 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00327 AC: 808 AN: 247420 Hom.: 25 AF XY: 0.00232 AC XY: 311 AN XY: 134304

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00150 AC: 2192 AN: 1460112 Hom.: 57 Cov.: 30 AF XY: 0.00128 AC XY: 930 AN XY: 726404

Gnomad4 AFR exome AF: 0.0488

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.0127 AC: 1940 AN: 152170 Hom.: 40 Cov.: 32 AF XY: 0.0122 AC XY: 911 AN XY: 74404

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00329 Hom.: 9

Bravo AF: 0.0139

ESP6500AA AF: 0.0446 AC: 168

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00404 AC: 488

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.86	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.24
Sift	Benign	0.31	T
Sift4G	Benign	0.27	T
Polyphen		0.056	B
Vest4		0.14
MVP		0.21
MPC		0.91
ClinPred		0.0090	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs114013865; hg19: chr17-60030333;