chrX-32518009-T-C

Variant names:

• chrX-32518009-T-C
• rs199588981
• ENST00000288447.9:c.2267A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_004006.3(DMD):​c.2291A>G​(p.Asn764Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000196 in 1,209,195 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 87 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. N764T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00020 (0 hom. 76 hem.)
• Consequence: DMD NM_004006.3 missense, splice_region
• Scores: Splicing: ADA: 0.9979
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.11
• Publications: 2 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 -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-32518009-T-C is Benign according to our data. Variant chrX-32518009-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288446.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000206 (23/111913) while in subpopulation EAS AF = 0.00451 (16/3549). AF 95% confidence interval is 0.00283. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 23 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.2291A>G	p.Asn764Ser	missense splice_region	Exon 18 of 79	NP_003997.2
	DMD	NM_004009.3		c.2279A>G	p.Asn760Ser	missense splice_region	Exon 18 of 79	NP_004000.1
	DMD	NM_000109.4		c.2267A>G	p.Asn756Ser	missense splice_region	Exon 18 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000288447.9	TSL:1	c.2267A>G	p.Asn756Ser	missense	Exon 18 of 18	ENSP00000288447.4
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.2291A>G	p.Asn764Ser	missense splice_region	Exon 18 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.2279A>G	p.Asn760Ser	missense splice_region	Exon 18 of 79	ENSP00000367948.2

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 23 AN: 111860 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000949

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00449

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000371 AC: 68 AN: 183211 AF XY: 0.000310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00375

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000195 AC: 214 AN: 1097282 Hom.: 0 Cov.: 29 AF XY: 0.000210 AC XY: 76 AN XY: 362712

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.000142 AC: 5 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00282 AC: 85 AN: 30185

South Asian (SAS) AF: 0.000240 AC: 13 AN: 54106

European-Finnish (FIN) AF: 0.000197 AC: 8 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.000108 AC: 91 AN: 841312

Other (OTH) AF: 0.000260 AC: 12 AN: 46068

GnomAD4 genome AF: 0.000206 AC: 23 AN: 111913 Hom.: 0 Cov.: 22 AF XY: 0.000323 AC XY: 11 AN XY: 34083

African (AFR) AF: 0.0000648 AC: 2 AN: 30867

American (AMR) AF: 0.0000948 AC: 1 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00451 AC: 16 AN: 3549

South Asian (SAS) AF: 0.000377 AC: 1 AN: 2656

European-Finnish (FIN) AF: 0.000165 AC: 1 AN: 6052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53160

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.000216 Hom.: 9

Bravo AF: 0.000178

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000338 AC: 41

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.83	T
PhyloP100		4.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.068
Sift	Benign	0.18	T
Sift4G	Uncertain	0.032	D
Polyphen		0.22	B
Vest4		0.30
MVP		0.79
MPC		0.084
ClinPred		0.021	T
GERP RS		3.9
gMVP		0.086
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199588981; hg19: chrX-32536126;