19-49818369-C-T

Variant names:

• chr19-49818369-C-T
• rs1209130181
• NM_030973.4:c.28C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030973.4(MED25):​c.28C>T​(p.Arg10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R10L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32982975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 236328 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000343 AC: 5 AN: 1456412 Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 4 AN XY: 724186

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00 AC: 0 AN: 85884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109470

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Mar 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 10 of the MED25 protein (p.Arg10Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MED25-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	0.30
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	.;.;T;T;T;.;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.36	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.69	.;.;.;.;N;.;N;.;.
PhyloP100		2.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.5	.;.;.;.;N;.;N;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	.;.;.;.;D;.;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		0.0010	.;.;.;.;B;.;.;.;.
Vest4		0.49
MutPred		0.38		Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);
MVP		0.55
MPC		1.0
ClinPred		0.71	D
GERP RS		2.5
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.18
gMVP		0.35
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1209130181; hg19: chr19-50321626;