Variant 17-6650072-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016060.3(MED31):c.113C>T(p.Ala38Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MED31
NM_016060.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.53

Variant links:

Genes affected

MED31 (HGNC:24260): (mediator complex subunit 31) Predicted to enable transcription coregulator activity and ubiquitin protein ligase activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within limb development and negative regulation of fibroblast proliferation. Predicted to be located in nucleoplasm. Predicted to be part of core mediator complex and mediator complex. [provided by Alliance of Genome Resources, Apr 2022]

MED31 links:

MED31 (HGNC:):

MED31 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED31	NM_016060.3 linkuse as main transcript	c.113C>T	p.Ala38Val	missense_variant	3/4	ENST00000225728.8	NP_057144.1	Q9Y3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MED31	ENST00000225728.8 linkuse as main transcript	c.113C>T	p.Ala38Val	missense_variant	3/4	1	NM_016060.3	ENSP00000225728.3	Q9Y3C7
MED31	ENST00000574128.1 linkuse as main transcript	c.-110C>T		5_prime_UTR_variant	3/4	3		ENSP00000459723.1	I3L2J1
MED31	ENST00000575197.1 linkuse as main transcript	c.106+284C>T		intron_variant		2		ENSP00000458248.1	I3L0P8
MED31	ENST00000575519.1 linkuse as main transcript	n.437C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000209

AC:

AN:

1436094

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714052

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74008

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.113C>T (p.A38V) alteration is located in exon 3 (coding exon 3) of the MED31 gene. This alteration results from a C to T substitution at nucleotide position 113, causing the alanine (A) at amino acid position 38 to be replaced by a valine (V). 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

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

3.7

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.80

MutPred

0.90

Loss of catalytic residue at A38 (P = 0.1646);

MVP

0.69

MPC

1.6

ClinPred

1.0

GERP RS

5.6

Varity_R

0.75

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over