chr19-49830172-C-T

Variant names:

• chr19-49830172-C-T
• rs950408993
• NM_030973.4:c.773C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030973.4(MED25):​c.773C>T​(p.Ser258Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S258S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23124114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.773C>T	p.Ser258Leu	missense_variant	Exon 7 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.773C>T	p.Ser258Leu	missense_variant	Exon 7 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.773C>T	p.Ser258Leu	missense_variant	Exon 7 of 18	1	NM_030973.4	ENSP00000326767.5
MED25	ENST00000538643.5	c.181-339C>T		intron_variant	Intron 2 of 12	1		ENSP00000437496.1
MED25	ENST00000595185.5	c.688+224C>T		intron_variant	Intron 6 of 6	1		ENSP00000470027.1
MED25	ENST00000593767.3	c.773C>T	p.Ser258Leu	missense_variant	Exon 7 of 18	3		ENSP00000470692.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Dec 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MED25-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 258 of the MED25 protein (p.Ser258Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.092
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.55	.;N
PhyloP100		2.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.15
Sift	Uncertain	0.029	.;D
Sift4G	Benign	0.64	T;T
Polyphen		0.61	.;P
Vest4		0.41
MutPred		0.22		Loss of glycosylation at S258 (P = 0.0063);Loss of glycosylation at S258 (P = 0.0063);
MVP		0.64
MPC		0.41
ClinPred		0.39	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.30
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs950408993; hg19: chr19-50333429; COSMIC: COSV57207699; COSMIC: COSV57207699;