19-49830825-G-T

Variant names:

• chr19-49830825-G-T
• rs146715554
• NM_030973.4:c.1039G>T

Variant summary

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

The NM_030973.4(MED25):​c.1039G>T​(p.Val347Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,996 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11

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.1039G>T	p.Val347Phe	missense_variant	Exon 9 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.1039G>T	p.Val347Phe	missense_variant	Exon 9 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.1039G>T	p.Val347Phe	missense_variant	Exon 9 of 18	1	NM_030973.4	ENSP00000326767.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247560 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000137 AC: 2 AN: 1460996 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	.;T;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.69	.;N;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	.;N;N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	.;D;D;.
Sift4G	Benign	0.093	T;D;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.78
MutPred		0.22		.;Loss of stability (P = 0.0605);.;.;
MVP		0.71
MPC		0.71
ClinPred		0.41	T
GERP RS		5.6
Varity_R		0.37
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs146715554; hg19: chr19-50334082;