rs104894791

Positions:

• chrX-31177932-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PS1_Moderate BS2_Supporting

The NM_004006.3(DMD):​c.10262C>T​(p.Ala3421Val) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,092,548 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense
• Scores: Splicing: ADA: 0.9922
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 4.16

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]

DMD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PS1: Transcript NM_004006.3 (DMD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.10262C>T	p.Ala3421Val	missense_variant	71/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.10262C>T	p.Ala3421Val	missense_variant	71/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000112 AC: 2 AN: 179063 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64315

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000251

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 12 AN: 1092548 Hom.: 0 Cov.: 29 AF XY: 0.00000558 AC XY: 2 AN XY: 358562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.000106 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2023	Observed in a 13 year old male with elevated CK levels, intellectual disability, and autism in published literature (Allen et al., 2018). No additional neuromuscular or cardiac findings were observed and only analysis of the DMD gene was completed.; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29610182, 8281150, 26350204, 25525159) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 25, 2022	- -

Becker muscular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 25, 2022

Variant summary: DMD c.10262C>T (p.Ala3421Val) results in a non-conservative amino acid change located in the Carboxy-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant alters the last nucleotide of exon 71 adjacent to the canonical splice donor site in Intron 71. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.1e-05 in 179063 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10262C>T has been reported in the literature in an individual with a reported diagnosis of BMD without mental retardation (Lenk_1993), Intellectual disability in the UK10K dataset (Grozeva_2015), and ID/autism with elevated CPK levels in a pediatric setting (Allen_2018). These reports do not provide unequivocal conclusions about association of the variant with Dystrophinopathies. One publication reports experimental evidence evaluating an impact on protein function and showed that this variant exhibited impaired interactions with a long noncoding RNA H19 (Zhang_2020). However, this result does not allow convincing conclusions about the pathogenic role of this variant. Three ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces alanine with valine at codon 3421 of the DMD protein (p.Ala3421Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of DMD-related conditions (PMID: 8281150, 26350204). This variant is also known as c.10238C>T (p.Ala3413Val). ClinVar contains an entry for this variant (Variation ID: 11276). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C25". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;T;.;T;.;.;.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;.;.;T;.;T;T;T;.;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N;.;N;.;N;.;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.42	T;.;T;.;D;.;D;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T
Polyphen		0.22, 0.95	.;.;B;.;P;.;.;.;B;.
Vest4		0.42
MutPred		0.58		.;.;.;.;.;.;Loss of glycosylation at P3422 (P = 0.0902);.;.;.;
MVP		0.96
MPC		0.066
ClinPred		0.72	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.080		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: rs104894791; hg19: chrX-31196049; COSMIC: COSV58902399; COSMIC: COSV58902399;