rs147538736

Positions:

chr19-49829924-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_030973.4(MED25):c.664C>T(p.Leu222=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000793 in 1,612,930 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 2 hom. )

Consequence

MED25
NM_030973.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.51

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024597228).

BP6

Variant 19-49829924-C-T is Benign according to our data. Variant chr19-49829924-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 215945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49829924-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.51 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000473 (72/152302) while in subpopulation NFE AF= 0.000941 (64/68020). AF 95% confidence interval is 0.000755. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4 linkuse as main transcript	c.664C>T	p.Leu222=	synonymous_variant	6/18	ENST00000312865.10
MED25	NM_001378355.1 linkuse as main transcript	c.664C>T	p.Leu222=	synonymous_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10 linkuse as main transcript	c.664C>T	p.Leu222=	synonymous_variant	6/18	1	NM_030973.4		Q71SY5-1
MED25	ENST00000595185.5 linkuse as main transcript	c.664C>T	p.Leu222=	synonymous_variant	6/7	1
MED25	ENST00000538643.5 linkuse as main transcript	c.181-587C>T		intron_variant		1			Q71SY5-6
MED25	ENST00000593767.3 linkuse as main transcript	c.664C>T	p.Leu222=	synonymous_variant	6/18	3		P1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000596

AC:

149

AN:

250116

Hom.:

AF XY:

0.000657

AC XY:

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000798

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000826

AC:

1207

AN:

1460628

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

576

AN XY:

726524

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000728

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000190

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000473

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000717

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.74

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.38

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.77

MutationTaster

Benign

1.0

D;D

Sift4G

Benign

0.26

Vest4

0.38

MVP

0.63

ClinPred

0.046

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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