rs185100172

chr19-49835774-C-T

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.1794C>T(p.Ala598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00757 in 1,608,894 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0078 (86 hom.)
• Consequence: MED25 NM_030973.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.705

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=-0.66).
• BP6: Variant 19-49835774-C-T is Benign according to our data. Variant chr19-49835774-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 215536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49835774-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.705 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00504 (768/152284) while in subpopulation SAS AF= 0.019 (92/4832). AF 95% confidence interval is 0.0159. There are 3 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.1794C>T	p.Ala598=	synonymous_variant	16/18	ENST00000312865.10
MED25	NM_001378355.1	c.1794C>T	p.Ala598=	synonymous_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.1794C>T	p.Ala598=	synonymous_variant	16/18	1	NM_030973.4

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 767 AN: 152166 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00716 AC: 1709 AN: 238760 Hom.: 16 AF XY: 0.00839 AC XY: 1098 AN XY: 130924

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00345

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.000388

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.00549

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00783 AC: 11405 AN: 1456610 Hom.: 86 Cov.: 32 AF XY: 0.00827 AC XY: 5991 AN XY: 724664

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00330

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0217

Gnomad4 FIN exome AF: 0.00522

Gnomad4 NFE exome AF: 0.00764

Gnomad4 OTH exome AF: 0.00742

GnomAD4 genome AF: 0.00504 AC: 768 AN: 152284 Hom.: 3 Cov.: 33 AF XY: 0.00526 AC XY: 392 AN XY: 74464

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.00423

Gnomad4 NFE AF: 0.00710

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00570 Hom.: 1

Bravo AF: 0.00470

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2015

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

Jan 29, 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

Nov 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	6.6
Dann	Benign	0.46

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

LitVar

Other links and lift over

dbSNP: rs185100172; hg19: chr19-50339031;