chr19-49830790-C-T

Position:

chr19-49830790-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_030973.4(MED25):c.1004C>T(p.Ala335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00665 in 1,613,014 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 41 hom. )

Consequence

MED25
NM_030973.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:10O:1

Conservation

PhyloP100: 1.05

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015774012).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00428 (651/152228) while in subpopulation NFE AF= 0.00725 (493/67998). AF 95% confidence interval is 0.00672. There are 3 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED25	NM_030973.4 linkuse as main transcript	c.1004C>T	p.Ala335Val	missense_variant	9/18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1 linkuse as main transcript	c.1004C>T	p.Ala335Val	missense_variant	9/18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10 linkuse as main transcript	c.1004C>T	p.Ala335Val	missense_variant	9/18	1	NM_030973.4	ENSP00000326767		Q71SY5-1
MED25	ENST00000538643.5 linkuse as main transcript	c.365C>T	p.Ala122Val	missense_variant	4/13	1		ENSP00000437496		Q71SY5-6
MED25	ENST00000595185.5 linkuse as main transcript	c.688+842C>T		intron_variant		1		ENSP00000470027
MED25	ENST00000593767.3 linkuse as main transcript	c.1004C>T	p.Ala335Val	missense_variant	9/18	3		ENSP00000470692	P1

Frequencies

GnomAD3 genomes

AF:

0.00427

AC:

650

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00384

AC:

952

AN:

247818

Hom.:

AF XY:

0.00384

AC XY:

517

AN XY:

134684

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000753

Gnomad FIN exome

AF:

0.00372

Gnomad NFE exome

AF:

0.00674

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00690

AC:

10082

AN:

1460786

Hom.:

Cov.:

AF XY:

0.00672

AC XY:

4886

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.000867

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000673

Gnomad4 FIN exome

AF:

0.00427

Gnomad4 NFE exome

AF:

0.00836

Gnomad4 OTH exome

AF:

0.00644

GnomAD4 genome

AF:

0.00428

AC:

651

AN:

152228

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000833

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.00725

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00610

Hom.:

Bravo

AF:

0.00413

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00364

AC:

442

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MED25: BS2 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Charcot-Marie-Tooth disease type 2B2

Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Oct 01, 2009	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

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

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Tip-toe gait

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 14, 2020

- -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

MED25-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

.;T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.094

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.74

T;T;T;.

M_CAP

Benign

0.031

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.55

.;N;.;.

MutationTaster

Benign

0.10

A;A

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.010

.;N;N;.

REVEL

Benign

0.29

Sift

Benign

0.17

.;T;T;.

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.021

.;B;.;.

Vest4

0.48

MVP

0.64

MPC

0.52

ClinPred

0.0077

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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