rs74863643

chr19-49819225-C-Gchr19-49819225-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030973.4(MED25):c.234C>G(p.Pro78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,614,180 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P78P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (224 hom., cov: 33)
  • Exomes 𝑓: 0.011 (682 hom.)
• Consequence: MED25 NM_030973.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.85

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=-0.73).
• BP6: Variant 19-49819225-C-G is Benign according to our data. Variant chr19-49819225-C-G is described in ClinVar as [Benign]. Clinvar id is 329878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49819225-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.234C>G	p.Pro78=	synonymous_variant	3/18	ENST00000312865.10
MED25	NM_001378355.1	c.234C>G	p.Pro78=	synonymous_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.234C>G	p.Pro78=	synonymous_variant	3/18	1	NM_030973.4

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5460 AN: 152230 Hom.: 223 Cov.: 33

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0772

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0310 AC: 7803 AN: 251418 Hom.: 424 AF XY: 0.0274 AC XY: 3718 AN XY: 135894

Gnomad AFR exome AF: 0.0793

Gnomad AMR exome AF: 0.0744

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0108 AC: 15822 AN: 1461832 Hom.: 682 Cov.: 33 AF XY: 0.0106 AC XY: 7691 AN XY: 727214

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.0761

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.0240

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.0210

GnomAD4 genome AF: 0.0360 AC: 5480 AN: 152348 Hom.: 224 Cov.: 33 AF XY: 0.0386 AC XY: 2873 AN XY: 74506

Gnomad4 AFR AF: 0.0777

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.0277

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.00336 Hom.: 1

Bravo AF: 0.0434

Asia WGS AF: 0.0730 AC: 252 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00284

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.8
Dann	Benign	0.79

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: rs74863643; hg19: chr19-50322482;