rs746210338

Positions:

• chr19-49830891-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_030973.4(MED25):​c.1101+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,602,452 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (4 hom.)
• Consequence: MED25 NM_030973.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001785
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.113

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000112 (163/1451302) while in subpopulation MID AF= 0.0054 (30/5558). AF 95% confidence interval is 0.00388. There are 4 homozygotes in gnomad4_exome. There are 105 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED25	NM_030973.4	c.1101+4G>A		splice_donor_region_variant, intron_variant		ENST00000312865.10
MED25	NM_001378355.1	c.1101+4G>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED25	ENST00000312865.10	c.1101+4G>A		splice_donor_region_variant, intron_variant		1	NM_030973.4

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 151036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.000154 AC: 37 AN: 240048 Hom.: 0 AF XY: 0.000222 AC XY: 29 AN XY: 130904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000994

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000370

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1451302 Hom.: 4 Cov.: 33 AF XY: 0.000145 AC XY: 105 AN XY: 722272

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151150 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 73918

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000149

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.000274

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2021

The c.1101+4G>A intronic alteration consists of a G to A substitution 4 nucleotides after exon 9 of the MED25 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change falls in intron 9 of the MED25 gene. It does not directly change the encoded amino acid sequence of the MED25 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs746210338, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MED25-related conditions. ClinVar contains an entry for this variant (Variation ID: 329881). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.020		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: rs746210338; hg19: chr19-50334148;