rs1555802134

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_030973.4(MED25):c.547G>A(p.Val183Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V183A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MED25
NM_030973.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30420852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4 link	c.547G>A	p.Val183Met	missense_variant	Exon 6 of 18	ENST00000312865.10	NP_112235.2	Q71SY5-1
MED25	NM_001378355.1 link	c.547G>A	p.Val183Met	missense_variant	Exon 6 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MED25	ENST00000312865.10 link	c.547G>A	p.Val183Met	missense_variant	Exon 6 of 18	1	NM_030973.4	ENSP00000326767.5	Q71SY5-1
MED25	ENST00000595185.5 link	c.547G>A	p.Val183Met	missense_variant	Exon 6 of 7	1		ENSP00000470027.1	M0QYR4
MED25	ENST00000538643.5 link	c.181-704G>A		intron_variant	Intron 2 of 12	1		ENSP00000437496.1	Q71SY5-6
MED25	ENST00000593767.3 link	c.547G>A	p.Val183Met	missense_variant	Exon 6 of 18	3		ENSP00000470692.3	M0QZQ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719630

African (AFR)

AF:

0.00

AC:

AN:

33220

American (AMR)

AF:

0.00

AC:

AN:

42716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25886

East Asian (EAS)

AF:

0.00

AC:

AN:

38894

South Asian (SAS)

AF:

0.00

AC:

AN:

84766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105770

Other (OTH)

AF:

0.00

AC:

AN:

59810

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Uncertain:1

Jun 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals with a MED25-related disease. This sequence change replaces valine with methionine at codon 183 of the MED25 protein (p.Val183Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MED25 function. The available evidence is currently insufficient to determine its role 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

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

.;T;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.083

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

0.55

.;N;.;.

PhyloP100

3.2

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.79

.;N;.;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.024

.;D;.;.

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.97

.;D;.;.

Vest4

0.72

MutPred

0.26

Gain of disorder (P = 0.12);Gain of disorder (P = 0.12);Gain of disorder (P = 0.12);Gain of disorder (P = 0.12);

MVP

0.80

MPC

1.1

ClinPred

0.68

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.76

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over