rs754765424

Variant names:

• chrX-32346044-G-C
• rs754765424
• NM_004006.3:c.5485C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004006.3(DMD):​c.5485C>G​(p.Gln1829Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,206,720 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 74 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. Q1829Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 9 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (0 hom. 65 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.03
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065455437).
• BP6: Variant X-32346044-G-C is Benign according to our data. Variant chrX-32346044-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 264026.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000234 (26/111000) while in subpopulation EAS AF = 0.0062 (22/3548). AF 95% confidence interval is 0.0042. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.5485C>G	p.Gln1829Glu	missense	Exon 39 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5473C>G	p.Gln1825Glu	missense	Exon 39 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.5461C>G	p.Gln1821Glu	missense	Exon 39 of 79	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.5485C>G	p.Gln1829Glu	missense	Exon 39 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5473C>G	p.Gln1825Glu	missense	Exon 39 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.1453C>G	p.Gln485Glu	missense	Exon 11 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.000234 AC: 26 AN: 110952 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000967

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00618

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000718 AC: 131 AN: 182437 AF XY: 0.000609

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000733

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00912

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000182 AC: 199 AN: 1095720 Hom.: 0 Cov.: 30 AF XY: 0.000180 AC XY: 65 AN XY: 361746

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.0000285 AC: 1 AN: 35127

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19323

East Asian (EAS) AF: 0.00549 AC: 165 AN: 30070

South Asian (SAS) AF: 0.00 AC: 0 AN: 54085

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840330

Other (OTH) AF: 0.000653 AC: 30 AN: 45970

GnomAD4 genome AF: 0.000234 AC: 26 AN: 111000 Hom.: 0 Cov.: 22 AF XY: 0.000270 AC XY: 9 AN XY: 33344

African (AFR) AF: 0.00 AC: 0 AN: 30646

American (AMR) AF: 0.0000966 AC: 1 AN: 10355

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2631

East Asian (EAS) AF: 0.00620 AC: 22 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5941

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52806

Other (OTH) AF: 0.00132 AC: 2 AN: 1510

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.000450

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.055
Sift	Benign	0.030	D
Sift4G	Benign	0.24	T
Polyphen		0.26	B
Vest4		0.17
MutPred		0.26		Loss of MoRF binding (P = 0.0534)
MVP		0.50
MPC		0.016
ClinPred		0.037	T
GERP RS		5.8
gMVP		0.070
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs754765424; hg19: chrX-32364161; COSMIC: COSV63734814;