Genetic Variant MED25:p.Val2Phe (chr19-49818345-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030973.4(MED25):c.4G>T(p.Val2Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,388 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MED25
NM_030973.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4 link	c.4G>T	p.Val2Phe	missense_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2	Q71SY5-1
MED25	NM_001378355.1 link	c.4G>T	p.Val2Phe	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>T	p.Val2Phe	missense_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5		Q71SY5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000490

AC:

AN:

203948

AF XY:

0.00000896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436388

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32892

American (AMR)

AF:

0.00

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:

0.0000118

AC:

AN:

84542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099208

Other (OTH)

AF:

0.00

AC:

AN:

59312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.69

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

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.4

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

PhyloP100

7.1

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-2.0

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

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.99

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

Vest4

0.54

MutPred

0.18

Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);

MVP

0.73

MPC

1.3

ClinPred

0.98

GERP RS

4.5

PromoterAI

0.055

Neutral

(source)

Varity_R

0.54

gMVP

0.39

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Computational scores

Splicing

Publications

Other links and lift over