Variant rs763039409 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_030973.4(MED25):c.1778_1779del(p.Gln593ArgfsTer?) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MED25
NM_030973.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.16

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 Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4 linkuse as main transcript	c.1778_1779del	p.Gln593ArgfsTer?	frameshift_variant	16/18	ENST00000312865.10
MED25	NM_001378355.1 linkuse as main transcript	c.1778_1779del	p.Gln593ArgfsTer174	frameshift_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10 linkuse as main transcript	c.1778_1779del	p.Gln593ArgfsTer?	frameshift_variant	16/18	1	NM_030973.4		Q71SY5-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000126

AC:

AN:

238374

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

130612

show subpopulations

Gnomad AFR exome

AF:

0.0000681

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000484

Gnomad NFE exome

AF:

0.00000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1458500

Hom.:

AF XY:

0.0000165

AC XY:

AN XY:

725520

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000385

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sensory neuropathy;C0240991:Sensory ataxia;C0856863:Broad-based gait;C1843859:Sensory ataxic neuropathy;C1858120:Generalized hypotonia;C2315100:Failure to thrive;C4021585:Impaired distal proprioception;C5574742:Decreased body weight

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2016

The current clinical and genetic evidence is not sufficient to establish whether this type of variant in MED25 causes disease. Therefore, this variant has been classified as a Variant of Uncertain Significance. This variant is present in population databases at a very low frequency (rs763039409, ExAC 0.01%) but has not been reported in the literature in individuals with a MED25-related disease. This sequence change deletes 2 nucleotide from exon 16 of the MED25 mRNA (c.1778_1779delAG), causing a frameshift at codon 593. This creates a new reading frame which does not encounter a premature termination codon, but is expected to result in disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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