chr19-49818345-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_030973.4(MED25):c.4G>C(p.Val2Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000308 in 1,588,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V2V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

MED25
NM_030973.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.07

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2B2
Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

MED25 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38739988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4 link	c.4G>C	p.Val2Leu	missense_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2	Q71SY5-1
MED25	NM_001378355.1 link	c.4G>C	p.Val2Leu	missense_variant	Exon 1 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10 link	c.4G>C	p.Val2Leu	missense_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5		Q71SY5-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000883

AC:

AN:

203948

AF XY:

0.0000806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000471

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000233

Gnomad OTH exome

AF:

0.000192

GnomAD4 exome

AF:

0.0000306

AC:

AN:

1436388

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

712972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32892

American (AMR)

AF:

0.000394

AC:

AN:

40606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25710

East Asian (EAS)

AF:

0.00

AC:

AN:

38260

South Asian (SAS)

AF:

0.0000828

AC:

AN:

84542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50386

Middle Eastern (MID)

AF:

0.000365

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.0000146

AC:

AN:

1099208

Other (OTH)

AF:

0.0000506

AC:

AN:

59312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.000196

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000752

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Jun 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2 of the MED25 protein (p.Val2Leu). This variant is present in population databases (rs780512266, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MED25-related conditions. ClinVar contains an entry for this variant (Variation ID: 476805). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

.;.;T;T;T;.;.;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D;.

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.39

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.4

.;.;.;.;L;.;L;.;.

PhyloP100

7.1

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.3

.;.;.;.;N;.;N;.;.

REVEL

Benign

0.29

Sift

Pathogenic

0.0

.;.;.;.;D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Polyphen

0.96

.;.;.;.;D;.;.;.;.

Vest4

0.43

MVP

0.77

MPC

0.93

ClinPred

0.21

GERP RS

4.5

PromoterAI

-0.056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.46

gMVP

0.27

Mutation Taster

=86/14

polymorphism

(source)

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

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chr19-49818345-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over