rs57854058

chr19-49836291-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_030973.4(MED25):c.2031G>A(p.Ala677=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00967 in 1,611,934 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (93 hom.)
• Consequence: MED25 NM_030973.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.73

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-49836291-G-A is Benign according to our data. Variant chr19-49836291-G-A is described in ClinVar as [Benign]. Clinvar id is 138200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49836291-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2172/152208) while in subpopulation AFR AF= 0.0285 (1182/41540). AF 95% confidence interval is 0.0271. There are 24 homozygotes in gnomad4. There are 965 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.2031G>A	p.Ala677=	synonymous_variant	17/18	ENST00000312865.10
MED25	NM_001378355.1	c.2031G>A	p.Ala677=	synonymous_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.2031G>A	p.Ala677=	synonymous_variant	17/18	1	NM_030973.4

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2167 AN: 152090 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00958

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00817 AC: 1965 AN: 240568 Hom.: 19 AF XY: 0.00765 AC XY: 1011 AN XY: 132112

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00754

Gnomad ASJ exome AF: 0.00951

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00135

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00960

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00919 AC: 13412 AN: 1459726 Hom.: 93 Cov.: 32 AF XY: 0.00892 AC XY: 6479 AN XY: 726146

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.00753

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00973

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0143 AC: 2172 AN: 152208 Hom.: 24 Cov.: 33 AF XY: 0.0130 AC XY: 965 AN XY: 74428

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00958

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0106 Hom.: 5

Bravo AF: 0.0156

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.00889

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.0
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs57854058; hg19: chr19-50339548; COSMIC: COSV57203835; COSMIC: COSV57203835;