X-32644145-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004006.3(DMD):c.1318G>A(p.Glu440Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,205,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E440E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 52 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 7.91

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010299444).
• BP6: Variant X-32644145-C-T is Benign according to our data. Variant chrX-32644145-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161221.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=3, Uncertain_significance=1}. Variant chrX-32644145-C-T is described in Lovd as [Likely_benign]. Variant chrX-32644145-C-T is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000197 (22/111578) while in subpopulation EAS AF= 0.00566 (20/3532). AF 95% confidence interval is 0.00375. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.1318G>A	p.Glu440Lys	missense_variant	11/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.1318G>A	p.Glu440Lys	missense_variant	11/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 23 AN: 111526 Hom.: 0 Cov.: 23 AF XY: 0.000237 AC XY: 8 AN XY: 33724

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000381

Gnomad EAS AF: 0.00593

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000470 AC: 84 AN: 178649 Hom.: 0 AF XY: 0.000393 AC XY: 25 AN XY: 63585

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000140

Gnomad EAS exome AF: 0.00528

Gnomad SAS exome AF: 0.000452

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.000455

GnomAD4 exome AF: 0.000160 AC: 175 AN: 1093785 Hom.: 0 Cov.: 29 AF XY: 0.000145 AC XY: 52 AN XY: 359683

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000312

Gnomad4 EAS exome AF: 0.00425

Gnomad4 SAS exome AF: 0.000619

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.000131

GnomAD4 genome AF: 0.000197 AC: 22 AN: 111578 Hom.: 0 Cov.: 23 AF XY: 0.000207 AC XY: 7 AN XY: 33786

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000381

Gnomad4 EAS AF: 0.00566

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000259 Hom.: 5

Bravo AF: 0.000200

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000527 AC: 64

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2019	Variant summary: DMD c.1318G>A (p.Glu440Lys) results in a conservative amino acid change located in the Spectrin/alpha-actinin repeat of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 195664 control chromosomes, predominantly at a frequency of 0.0053 within the East Asian subpopulation in the gnomAD database, including 24 hemizygotes. This frequency is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies, strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1318G>A has been reported in the literature in a family affected with Becker muscular dystrophy and it was found in cis with a pathogenic variant (DMD deletion of exons 45 to 53) in 3 affected males and 2 female carriers (Li_2012), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign and a submission derived from reference population cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2016	- -

Becker muscular dystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Dystrophin deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 23, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2014

The variant is found in CARDIOMYOPATHY panel(s). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2019

This alteration is classified as likely 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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		0.94, 0.14	.;P;.;.;B
Vest4		0.62
MVP		0.84
MPC		0.028
ClinPred		0.11	T
GERP RS		5.8
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs189143447; hg19: chrX-32662262;