19-16577021-C-T

Position:

chr19-16577021-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000263390.8(MED26):c.809G>A(p.Arg270His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,608,452 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0021 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 8 hom. )

Consequence

MED26
ENST00000263390.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.29

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:

LOC105372295 (HGNC:):

LOC105372295 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006079614).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00208 (317/152348) while in subpopulation AMR AF= 0.0195 (298/15300). AF 95% confidence interval is 0.0177. There are 9 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 317 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MED26	NM_004831.5 linkuse as main transcript	c.809G>A	p.Arg270His	missense_variant	3/3	ENST00000263390.8	NP_004822.2
LOC105372295	XR_936359.3 linkuse as main transcript	n.475-1145C>T		intron_variant, non_coding_transcript_variant
LOC105372295	XR_936360.3 linkuse as main transcript	n.260-1145C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED26	ENST00000263390.8 linkuse as main transcript	c.809G>A	p.Arg270His	missense_variant	3/3	1	NM_004831.5	ENSP00000263390	P1	O95402-1
MED26	ENST00000611692.4 linkuse as main transcript	c.*174G>A		3_prime_UTR_variant	4/4	1		ENSP00000484490		O95402-2
MED26	ENST00000597244.1 linkuse as main transcript	n.1757G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0195

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:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000872

AC:

214

AN:

245470

Hom.:

AF XY:

0.000684

AC XY:

AN XY:

133054

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00570

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.000834

GnomAD4 exome

AF:

0.000229

AC:

333

AN:

1456104

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

154

AN XY:

723434

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.00622

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000343

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.00208

AC:

317

AN:

152348

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

223

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.00222

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Sep 15, 2021

The c.809G>A (p.R270H) alteration is located in exon 3 (coding exon 3) of the MED26 gene. This alteration results from a G to A substitution at nucleotide position 809, causing the arginine (R) at amino acid position 270 to be replaced by a histidine (H). 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

0.099

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.77

M_CAP

Benign

0.0049

MetaRNN

Benign

0.0061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

REVEL

Benign

0.10

Sift

Benign

0.039

Sift4G

Benign

0.23

Polyphen

0.0020

Vest4

0.089

MVP

0.19

MPC

0.37

ClinPred

0.013

GERP RS

2.5

Varity_R

0.056

gMVP

0.22

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