19-49818345-G-T

Variant names:

• chr19-49818345-G-T
• rs780512266
• NM_030973.4:c.4G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030973.4(MED25):​c.4G>T​(p.Val2Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,388 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.4G>T	p.Val2Phe	missense_variant	Exon 1 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.4G>T	p.Val2Phe	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.4G>T	p.Val2Phe	missense_variant	Exon 1 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000490 AC: 1 AN: 203948 Hom.: 0 AF XY: 0.00000896 AC XY: 1 AN XY: 111666

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 SAS exome AF: 0.0000351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436388 Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1 AN XY: 712972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;T;T;T;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.4	.;.;.;.;L;.;L;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.0	.;.;.;.;N;.;N;.;.
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.;.;.
Vest4		0.54
MutPred		0.18		Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);Gain of glycosylation at P3 (P = 0.1827);
MVP		0.73
MPC		1.3
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs780512266; hg19: chr19-50321602;