rs752332058

Variant names:

• chrX-31121883-CTCTGCCCAAATCA-C
• rs752332058
• ENST00000378723.7:c.1845_1857delTGATTTGGGCAGA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_004021.3(DMD):​c.3669_3681delTGATTTGGGCAGA​(p.Asp1223GlufsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,208,174 control chromosomes in the GnomAD database, including 4 homozygotes. There are 140 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., 38 hem., cov: 23)
  • Exomes 𝑓: 0.00032 (0 hom. 102 hem.)
• Consequence: DMD NM_004021.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 8.53
• Publications: 3 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 -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0169 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant X-31121883-CTCTGCCCAAATCA-C is Benign according to our data. Variant chrX-31121883-CTCTGCCCAAATCA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201754.
• BS2: High AC in GnomAd4 at 155 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004021.3. 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.*23_*35delTGATTTGGGCAGA		3_prime_UTR	Exon 79 of 79	NP_003997.2	P11532-1
	DMD	NM_004021.3		c.3669_3681delTGATTTGGGCAGA	p.Asp1223GlufsTer6	frameshift	Exon 35 of 35	NP_004012.2	P11532-14
	DMD	NM_004022.3		c.3630_3642delTGATTTGGGCAGA	p.Asp1210GlufsTer6	frameshift	Exon 34 of 34	NP_004013.2	P11532-15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000378723.7	TSL:1	c.1845_1857delTGATTTGGGCAGA	p.Asp615GlufsTer6	frameshift	Exon 17 of 17	ENSP00000367997.3	P11532-6
	DMD	ENST00000361471.8	TSL:1	c.1806_1818delTGATTTGGGCAGA	p.Asp602GlufsTer6	frameshift	Exon 16 of 16	ENSP00000354464.4	P11532-5
	DMD	ENST00000378680.6	TSL:1	c.1515_1527delTGATTTGGGCAGA	p.Asp505GlufsTer6	frameshift	Exon 13 of 13	ENSP00000367951.2	P11532-9

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 155 AN: 112359 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000488

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000695

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000257 AC: 47 AN: 182672 AF XY: 0.000193

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000507

Gnomad NFE exome AF: 0.000454

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000318 AC: 349 AN: 1095815 Hom.: 0 AF XY: 0.000282 AC XY: 102 AN XY: 361619

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26323

American (AMR) AF: 0.0000284 AC: 1 AN: 35168

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 54093

European-Finnish (FIN) AF: 0.000718 AC: 29 AN: 40389

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.000358 AC: 301 AN: 840193

Other (OTH) AF: 0.000391 AC: 18 AN: 45990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00138 AC: 155 AN: 112359 Hom.: 4 Cov.: 23 AF XY: 0.00110 AC XY: 38 AN XY: 34559

African (AFR) AF: 0.00 AC: 0 AN: 30938

American (AMR) AF: 0.00 AC: 0 AN: 10611

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2759

European-Finnish (FIN) AF: 0.000488 AC: 3 AN: 6147

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000695 AC: 37 AN: 53231

Other (OTH) AF: 0.00132 AC: 2 AN: 1514

Alfa AF: 0.000218 Hom.: 2

Bravo AF: 0.00211

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not specified (5)
-	-	3	not provided (3)
-	-	1	DMD-related disorder (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Intellectual disability (1)
-	1	-	Primary familial dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5
Mutation Taster		=24/176	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs752332058; hg19: chrX-31140000; COSMIC: COSV58921107;