19-49829898-T-C

Position:

chr19-49829898-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_030973.4(MED25):c.638T>C(p.Val213Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

MED25
NM_030973.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.94

Variant links:

Genes affected

MED25 (HGNC:28845): (mediator complex subunit 25) This gene encodes a component of the transcriptional coactivator complex termed the Mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes. The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. Mutations in this gene are associated with Charcot-Marie-Tooth disease type 2B2. [provided by RefSeq, Apr 2010]

MED25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016260952).

BP6

Variant 19-49829898-T-C is Benign according to our data. Variant chr19-49829898-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 409954.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000742 (113/152282) while in subpopulation AFR AF= 0.00248 (103/41570). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED25	NM_030973.4 linkuse as main transcript	c.638T>C	p.Val213Ala	missense_variant	6/18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1 linkuse as main transcript	c.638T>C	p.Val213Ala	missense_variant	6/18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10 linkuse as main transcript	c.638T>C	p.Val213Ala	missense_variant	6/18	1	NM_030973.4	ENSP00000326767		Q71SY5-1
MED25	ENST00000595185.5 linkuse as main transcript	c.638T>C	p.Val213Ala	missense_variant	6/7	1		ENSP00000470027
MED25	ENST00000538643.5 linkuse as main transcript	c.181-613T>C		intron_variant		1		ENSP00000437496		Q71SY5-6
MED25	ENST00000593767.3 linkuse as main transcript	c.638T>C	p.Val213Ala	missense_variant	6/18	3		ENSP00000470692	P1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000172

AC:

AN:

249966

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.00244

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1461184

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.00263

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152282

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000611

Hom.:

Bravo

AF:

0.000933

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

- -

MED25-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;T;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.34

.;N;.

MutationTaster

Benign

0.66

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.84

.;N;.

REVEL

Benign

0.28

Sift

Benign

0.041

.;D;.

Sift4G

Benign

0.42

T;T;T

Polyphen

0.63

.;P;.

Vest4

0.52

MVP

0.71

MPC

0.70

ClinPred

0.046

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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