19-49828983-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_030973.4(MED25):c.418C>T(p.Arg140Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MED25
NM_030973.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 1.84

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.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-49828983-C-T is Pathogenic according to our data. Variant chr19-49828983-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 183670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49828983-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4 linkuse as main transcript	c.418C>T	p.Arg140Trp	missense_variant	5/18	ENST00000312865.10
MED25	NM_001378355.1 linkuse as main transcript	c.418C>T	p.Arg140Trp	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10 linkuse as main transcript	c.418C>T	p.Arg140Trp	missense_variant	5/18	1	NM_030973.4		Q71SY5-1
MED25	ENST00000595185.5 linkuse as main transcript	c.418C>T	p.Arg140Trp	missense_variant	5/7	1
MED25	ENST00000538643.5 linkuse as main transcript	c.181-1528C>T		intron_variant		1			Q71SY5-6
MED25	ENST00000593767.3 linkuse as main transcript	c.418C>T	p.Arg140Trp	missense_variant	5/18	3		P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.0000119

AC:

AN:

251360

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000185

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000524

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

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 140 of the MED25 protein (p.Arg140Trp). This variant is present in population databases (rs781140315, gnomAD 0.006%). This missense change has been observed in individual(s) with MED25-related conditions (PMID: 25527630). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183670). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 23, 2024

This substitution has been identified and confirmed in compound heterozygosity with a nonsense variant in a proband presenting neurodevelopmental delay, epilepsy and dysmorphic features reminiscent of Basel-Vanagaite-Smirin-Yosef syndrome (Mendelics). It is present at a very low frequency in gnomAD database - MAF 0.00002169 (v4.1.0) and has been previously described in the medical literature in homozygosity segregating with intellectual deficiency in seven individuals from a highly consanguineous Brazilian family (PMID: 25527630). -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.29

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Benign

-0.095

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.75

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.52

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.80

Sift4G

Uncertain

0.011

D;D;D;D;D

Polyphen

1.0

.;.;D;.;.

Vest4

0.86

MutPred

0.67

Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);

MVP

0.30

MPC

1.2

ClinPred

0.96

GERP RS

2.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.6

Varity_R

0.41

gMVP

0.86

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

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