NM_030973.4:c.1727C>T

Variant names:

• chr19-49835586-C-T
• rs193291405
• NM_030973.4:c.1727C>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.1727C>T​(p.Ala576Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A576G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65
• Publications: 4 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=0.07769817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.1727C>T	p.Ala576Val	missense_variant	Exon 15 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.1727C>T	p.Ala576Val	missense_variant	Exon 15 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.1727C>T	p.Ala576Val	missense_variant	Exon 15 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412856 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 698358

African (AFR) AF: 0.00 AC: 0 AN: 32270

American (AMR) AF: 0.00 AC: 0 AN: 38264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25308

East Asian (EAS) AF: 0.00 AC: 0 AN: 36980

South Asian (SAS) AF: 0.00 AC: 0 AN: 80360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1087294

Other (OTH) AF: 0.00 AC: 0 AN: 58364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Aug 22, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with valine at codon 576 of the MED25 protein (p.Ala576Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.084	.;T;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.78	T;T;T;.;.
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;.;.;.
PhyloP100		1.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.30	.;N;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.28	.;T;T;.;.
Sift4G	Benign	0.38	T;T;T;T;.
Polyphen		0.041	.;B;.;.;.
Vest4		0.38
MutPred		0.31		.;Loss of methylation at R577 (P = 0.1624);.;.;.;
MVP		0.45
MPC		0.12
ClinPred		0.17	T
GERP RS		4.7
Varity_R		0.035
gMVP		0.30
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs193291405; hg19: chr19-50338843;