rs79635160

Positions:

• chr19-49835527-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030973.4(MED25):​c.1675-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,550,226 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (11 hom.)
• Consequence: MED25 NM_030973.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002592
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.26

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-49835527-C-T is Benign according to our data. Variant chr19-49835527-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 329886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49835527-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0016 (243/152344) while in subpopulation EAS AF= 0.0255 (132/5184). AF 95% confidence interval is 0.0219. There are 4 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.1675-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000312865.10
MED25	NM_001378355.1	c.1675-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.1675-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_030973.4

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152226 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00308 AC: 500 AN: 162230 Hom.: 5 AF XY: 0.00310 AC XY: 269 AN XY: 86848

Gnomad AFR exome AF: 0.000110

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.000128

Gnomad EAS exome AF: 0.0280

Gnomad SAS exome AF: 0.000797

Gnomad FIN exome AF: 0.000447

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.00142 AC: 1988 AN: 1397882 Hom.: 11 Cov.: 33 AF XY: 0.00147 AC XY: 1017 AN XY: 689758

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.0000407

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.000786

Gnomad4 FIN exome AF: 0.000474

Gnomad4 NFE exome AF: 0.000822

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152344 Hom.: 4 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74492

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000890 Hom.: 0

Bravo AF: 0.00184

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 20, 2019

- -

Charcot-Marie-Tooth disease type 2B2;C4225323:Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 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

Sep 08, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0040
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: rs79635160; hg19: chr19-50338784;