chrX-32345998-C-T

Variant names:

• chrX-32345998-C-T
• rs751221923
• NM_004006.3:c.5531G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_004006.3(DMD):​c.5531G>A​(p.Arg1844Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000133 in 1,207,338 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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. R1844R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom. 8 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.18
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21633348).
• BP6: Variant X-32345998-C-T is Benign according to our data. Variant chrX-32345998-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409932.
• BS2: High AC in GnomAdExome4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.5531G>A	p.Arg1844Gln	missense	Exon 39 of 79	NP_003997.2
	DMD	NM_004009.3		c.5519G>A	p.Arg1840Gln	missense	Exon 39 of 79	NP_004000.1
	DMD	NM_000109.4		c.5507G>A	p.Arg1836Gln	missense	Exon 39 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.5531G>A	p.Arg1844Gln	missense	Exon 39 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.5519G>A	p.Arg1840Gln	missense	Exon 39 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.1499G>A	p.Arg500Gln	missense	Exon 11 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110922 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182420 AF XY: 0.0000298

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1096416 Hom.: 0 Cov.: 30 AF XY: 0.0000221 AC XY: 8 AN XY: 362402

African (AFR) AF: 0.0000759 AC: 2 AN: 26353

American (AMR) AF: 0.00 AC: 0 AN: 35132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00 AC: 0 AN: 30084

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54095

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 840985

Other (OTH) AF: 0.00 AC: 0 AN: 45990

GnomAD4 genome AF: 0.00000902 AC: 1 AN: 110922 Hom.: 0 Cov.: 23 AF XY: 0.0000301 AC XY: 1 AN XY: 33208

African (AFR) AF: 0.0000327 AC: 1 AN: 30571

American (AMR) AF: 0.00 AC: 0 AN: 10378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 231

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52824

Other (OTH) AF: 0.00 AC: 0 AN: 1489

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (1)
-	1	-	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.082
Sift	Benign	0.20	T
Sift4G	Benign	0.11	T
Polyphen		0.91	P
Vest4		0.41
MutPred		0.28		Loss of MoRF binding (P = 0.0151)
MVP		0.69
MPC		0.038
ClinPred		0.59	D
GERP RS		5.8
gMVP		0.28
Mutation Taster		=93/7	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: rs751221923; hg19: chrX-32364115;