chr19-49818399-T-A

Position:

• chr19-49818399-T-A

Variant summary

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

The NM_030973.4(MED25):​c.58T>A​(p.Phe20Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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/exons	MANE	Protein	UniProt
MED25	NM_030973.4	c.58T>A	p.Phe20Ile	missense_variant	1/18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.58T>A	p.Phe20Ile	missense_variant	1/18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.58T>A	p.Phe20Ile	missense_variant	1/18	1	NM_030973.4	ENSP00000326767

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2022

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. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MED25-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 20 of the MED25 protein (p.Phe20Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;.;T;T;D;.;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	.;.;.;.;M;.;M;.;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.97	D
PROVEAN	Uncertain	-3.6	.;.;.;.;D;.;N;.;.
REVEL	Benign	0.27
Sift	Benign	0.098	.;.;.;.;T;.;T;.;.
Sift4G	Benign	0.092	T;T;T;T;T;T;D;T;T
Polyphen		0.82	.;.;.;.;P;.;.;.;.
Vest4		0.80
MutPred		0.31		Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);Loss of catalytic residue at F20 (P = 0.0024);
MVP		0.71
MPC		1.4
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.64
gMVP		0.75

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50321656;