chr19-49828497-C-T

Position:

• chr19-49828497-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 2P and 15B. PM2 BP4_Moderate BP6_Very_Strong BP7 BS1

The ENST00000312865.10(MED25):​c.354C>T​(p.Leu118=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: MED25 ENST00000312865.10 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.111

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 -13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 19-49828497-C-T is Benign according to our data. Variant chr19-49828497-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 329879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00108 (164/152326) while in subpopulation NFE AF= 0.00168 (114/68030). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED25	NM_030973.4	c.354C>T	p.Leu118=	synonymous_variant	4/18	ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.354C>T	p.Leu118=	synonymous_variant	4/18		NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.354C>T	p.Leu118=	synonymous_variant	4/18	1	NM_030973.4	ENSP00000326767
MED25	ENST00000595185.5	c.354C>T	p.Leu118=	synonymous_variant	4/7	1		ENSP00000470027
MED25	ENST00000538643.5	c.181-2014C>T		intron_variant		1		ENSP00000437496
MED25	ENST00000593767.3	c.354C>T	p.Leu118=	synonymous_variant	4/18	3		ENSP00000470692	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00109 AC: 274 AN: 251424 Hom.: 0 AF XY: 0.00107 AC XY: 146 AN XY: 135916

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00136 AC: 1994 AN: 1461802 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 978 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74482

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MED25: BP4, BP7 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 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

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs145574885; hg19: chr19-50331754;