chr19-16576694-G-A

Position:

chr19-16576694-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000263390.8(MED26):c.1136C>T(p.Ala379Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

MED26
ENST00000263390.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.937

Variant links:

Genes affected

MED26 (HGNC:2376): (mediator complex subunit 26) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. [provided by RefSeq, Jul 2008]

MED26 links:

ENSG00000141979 (HGNC:):

ENSG00000141979 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023709804).

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED26	NM_004831.5 linkuse as main transcript	c.1136C>T	p.Ala379Val	missense_variant	3/3	ENST00000263390.8	NP_004822.2	O95402-1
LOC105372295	XR_936359.3 linkuse as main transcript	n.475-1472G>A		intron_variant
LOC105372295	XR_936360.3 linkuse as main transcript	n.260-1472G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MED26	ENST00000263390.8 linkuse as main transcript	c.1136C>T	p.Ala379Val	missense_variant	3/3	1	NM_004831.5	ENSP00000263390.3	O95402-1
MED26	ENST00000611692.4 linkuse as main transcript	c.*501C>T		3_prime_UTR_variant	4/4	1		ENSP00000484490.1	O95402-2
ENSG00000141979	ENST00000409035.1 linkuse as main transcript	n.1160C>T		non_coding_transcript_exon_variant	4/12	2		ENSP00000386951.2	B8ZZF3
MED26	ENST00000597244.1 linkuse as main transcript	n.2084C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000216

AC:

AN:

249612

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000338

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461302

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000225

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000177

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000271

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

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

Apr 12, 2022

The c.1136C>T (p.A379V) alteration is located in exon 3 (coding exon 3) of the MED26 gene. This alteration results from a C to T substitution at nucleotide position 1136, causing the alanine (A) at amino acid position 379 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

Benign

0.082

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.040

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.70

M_CAP

Benign

0.0028

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.0

REVEL

Benign

0.089

Sift

Benign

0.41

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.069

MVP

0.12

MPC

0.30

ClinPred

0.015

GERP RS

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.030

gMVP

0.12

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