rs371157406

chr19-49836348-G-Achr19-49836348-G-C

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.2088G>A(p.Leu696=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,609,380 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: MED25 NM_030973.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 0.690

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=-0.5).
• BP6: Variant 19-49836348-G-A is Benign according to our data. Variant chr19-49836348-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 221058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49836348-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (365/152298) while in subpopulation NFE AF= 0.00351 (239/68006). AF 95% confidence interval is 0.00315. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.2088G>A	p.Leu696=	synonymous_variant	17/18	ENST00000312865.10
MED25	NM_001378355.1	c.2088G>A	p.Leu696=	synonymous_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.2088G>A	p.Leu696=	synonymous_variant	17/18	1	NM_030973.4

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00268 AC: 632 AN: 235818 Hom.: 2 AF XY: 0.00251 AC XY: 324 AN XY: 129278

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000976

Gnomad FIN exome AF: 0.00408

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00304 AC: 4424 AN: 1457082 Hom.: 8 Cov.: 32 AF XY: 0.00297 AC XY: 2149 AN XY: 724582

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00323

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000759

Gnomad4 FIN exome AF: 0.00449

Gnomad4 NFE exome AF: 0.00343

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74458

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00284 Hom.: 0

Bravo AF: 0.00232

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MED25: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Polyneuropathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

-

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

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 30, 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

Mar 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.4
Dann	Benign	0.45

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: rs371157406; hg19: chr19-50339605; COSMIC: COSV57204599; COSMIC: COSV57204599;