rs147474070

Variant names:

• chrX-32411750-G-A
• rs147474070
• NM_004006.3:c.4233+2C>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_004006.3(DMD):​c.4233+2C>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000821 in 1,208,749 control chromosomes in the GnomAD database, including 1 homozygotes. There are 291 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., 21 hem., cov: 22)
  • Exomes 𝑓: 0.00084 (1 hom. 270 hem.)
• Consequence: DMD NM_004006.3 splice_donor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 4.04

Genes affected

DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014650027 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: cagGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant X-32411750-G-A is Benign according to our data. Variant chrX-32411750-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94616.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=6, Uncertain_significance=1}. Variant chrX-32411750-G-A is described in Lovd as [Benign]. Variant chrX-32411750-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000637 (71/111497) while in subpopulation AMR AF= 0.00182 (19/10454). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.4233+2C>T		splice_donor_variant, intron_variant	Intron 30 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.4233+2C>T		splice_donor_variant, intron_variant	Intron 30 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 71 AN: 111443 Hom.: 0 Cov.: 22 AF XY: 0.000624 AC XY: 21 AN XY: 33647

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00182

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000847

Gnomad OTH AF: 0.000667

GnomAD3 exomes AF: 0.000651 AC: 119 AN: 182827 Hom.: 1 AF XY: 0.000637 AC XY: 43 AN XY: 67533

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.000675

Gnomad OTH exome AF: 0.000886

GnomAD4 exome AF: 0.000839 AC: 921 AN: 1097252 Hom.: 1 Cov.: 31 AF XY: 0.000744 AC XY: 270 AN XY: 362738

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.000258

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000741

Gnomad4 NFE exome AF: 0.000953

Gnomad4 OTH exome AF: 0.000803

GnomAD4 genome AF: 0.000637 AC: 71 AN: 111497 Hom.: 0 Cov.: 22 AF XY: 0.000623 AC XY: 21 AN XY: 33711

Gnomad4 AFR AF: 0.000163

Gnomad4 AMR AF: 0.00182

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000847

Gnomad4 OTH AF: 0.000659

Alfa AF: 0.000734 Hom.: 34

Bravo AF: 0.000582

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000503 AC: 61

EpiCase AF: 0.000600

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Mar 05, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17259292, 23871722, 26185613, 25163546, 28701297, 31216405) -

Dec 12, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2017

Baylor Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

May 28, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DMD c.4233+2C>T is located in a canonical splice-site and is predicted by several computational tools to strengthen a canonical 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00065 in 182827 control chromosomes in the gnomAD database, including 1 homozygote and 43 hemizygotes. The observed variant frequency is approximately 59-fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is benign. c.4233+2C>T has been reported in the literature in individuals affected with dilated cardiomyopathy and vacuolar myopathy, without strong evidence for causality (e.g. Haas_2015, Bodian_2017, Mair_2020). In at least one of these reports the variant was also detected in an unaffected parent of the proband. These reports do not provide unequivocal conclusions about association of the variant with Dystrophinopathies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Dilated cardiomyopathy 3B Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1

Oct 18, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 28, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DMD-related disorder Benign:1

Jun 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Sep 20, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.95
FATHMM_MKL	Benign	0.69	D
GERP RS		3.7

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: rs147474070; hg19: chrX-32429867;