rs886043324

Variant names:

• chrX-31147480-T-C
• rs886043324
• NM_004006.3:c.10592A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_004006.3(DMD):​c.10592A>G​(p.His3531Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,201,560 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3531D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000025 (0 hom. 16 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 8.02
• Publications: 0 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

ENSG00000297249 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31522906).
• BP6: Variant X-31147480-T-C is Benign according to our data. Variant chrX-31147480-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286157.
• BS2: High AC in GnomAdExome4 at 27 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.10592A>G	p.His3531Arg	missense	Exon 75 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.10580A>G	p.His3527Arg	missense	Exon 75 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.10568A>G	p.His3523Arg	missense	Exon 75 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.10592A>G	p.His3531Arg	missense	Exon 75 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378723.7	TSL:1	c.1388A>G	p.His463Arg	missense	Exon 14 of 17	ENSP00000367997.3	P11532-6
	DMD	ENST00000361471.8	TSL:1	c.1349A>G	p.His450Arg	missense	Exon 13 of 16	ENSP00000354464.4	P11532-5

Frequencies

GnomAD3 genomes AF: 0.0000369 AC: 4 AN: 108351 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000994

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000169 AC: 3 AN: 177679 AF XY: 0.0000319

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000382

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 27 AN: 1093209 Hom.: 0 Cov.: 29 AF XY: 0.0000446 AC XY: 16 AN XY: 358827

African (AFR) AF: 0.00 AC: 0 AN: 26324

American (AMR) AF: 0.0000285 AC: 1 AN: 35073

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30100

South Asian (SAS) AF: 0.00 AC: 0 AN: 53783

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40405

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.0000298 AC: 25 AN: 838174

Other (OTH) AF: 0.0000218 AC: 1 AN: 45889

GnomAD4 genome AF: 0.0000369 AC: 4 AN: 108351 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 30787

African (AFR) AF: 0.0000338 AC: 1 AN: 29592

American (AMR) AF: 0.0000994 AC: 1 AN: 10060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2614

East Asian (EAS) AF: 0.00 AC: 0 AN: 3479

South Asian (SAS) AF: 0.00 AC: 0 AN: 2355

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5539

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.0000382 AC: 2 AN: 52351

Other (OTH) AF: 0.00 AC: 0 AN: 1458

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.61	T
PhyloP100		8.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.15
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.19	B
Vest4		0.61
MutPred		0.24		Gain of MoRF binding (P = 0.0415)
MVP		0.84
MPC		0.037
ClinPred		0.76	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.69
Mutation Taster		=77/23	polymorphism

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: rs886043324; hg19: chrX-31165597;