19-49829918-A-T

Variant names:

• chr19-49829918-A-T
• rs905166588
• NM_030973.4:c.658A>T

Variant summary

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

The NM_030973.4(MED25):​c.658A>T​(p.Met220Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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.658A>T	p.Met220Leu	missense_variant	Exon 6 of 18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.658A>T	p.Met220Leu	missense_variant	Exon 6 of 18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.658A>T	p.Met220Leu	missense_variant	Exon 6 of 18	1	NM_030973.4	ENSP00000326767.5
MED25	ENST00000595185.5	c.658A>T	p.Met220Leu	missense_variant	Exon 6 of 7	1		ENSP00000470027.1
MED25	ENST00000538643.5	c.181-593A>T		intron_variant	Intron 2 of 12	1		ENSP00000437496.1
MED25	ENST00000593767.3	c.658A>T	p.Met220Leu	missense_variant	Exon 6 of 18	3		ENSP00000470692.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461048 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726832

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 220 of the MED25 protein (p.Met220Leu). 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. ClinVar contains an entry for this variant (Variation ID: 476808). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.93
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.25	T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.76	T
Sift4G	Benign	0.28	T
Vest4		0.78
MVP		0.52
ClinPred		0.77	D
GERP RS		5.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs905166588; hg19: chr19-50333175;