rs1555802134

chr19-49829807-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_030973.4(MED25):c.547G>A(p.Val183Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30420852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.547G>A	p.Val183Met	missense_variant	6/18	ENST00000312865.10
MED25	NM_001378355.1	c.547G>A	p.Val183Met	missense_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.547G>A	p.Val183Met	missense_variant	6/18	1	NM_030973.4
MED25	ENST00000595185.5	c.547G>A	p.Val183Met	missense_variant	6/7	1
MED25	ENST00000538643.5	c.181-704G>A		intron_variant		1
MED25	ENST00000593767.3	c.547G>A	p.Val183Met	missense_variant	6/18	3		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448288 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 719630

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Invitae

Jun 17, 2017

In summary, this variant has uncertain impact on MED25 function. The available evidence is currently insufficient to determine its role 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 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 with a MED25-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 183 of the MED25 protein (p.Val183Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	0.66	D;D
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.97	.;D;.;.
Vest4		0.72
MutPred		0.26		Gain of disorder (P = 0.12);Gain of disorder (P = 0.12);Gain of disorder (P = 0.12);Gain of disorder (P = 0.12);
MVP		0.80
MPC		1.1
ClinPred		0.68	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.76

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: rs1555802134; hg19: chr19-50333064;