rs72466595

Variant names:

• chrX-31929680-G-A
• rs72466595
• NM_004006.3:c.6828C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-31929680-G-A
• chrX-31929680-G-C
• chrX-31929680-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004021.3(DMD):​c.-553C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000715 in 1,209,058 control chromosomes in the GnomAD database, including 1 homozygotes. There are 285 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).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., 13 hem., cov: 22)
  • Exomes 𝑓: 0.00075 (1 hom. 272 hem.)
• Consequence: DMD NM_004021.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.0140
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.044).
• BP6: Variant X-31929680-G-A is Benign according to our data. Variant chrX-31929680-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94747.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000748 (821/1097715) while in subpopulation NFE AF = 0.00088 (741/841697). AF 95% confidence interval is 0.000828. There are 1 homozygotes in GnomAdExome4. There are 272 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 43 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.6828C>T	p.Pro2276Pro	synonymous	Exon 47 of 79	NP_003997.2
	DMD	NM_004021.3		c.-553C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 35	NP_004012.2
	DMD	NM_004022.3		c.-553C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 34	NP_004013.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.6828C>T	p.Pro2276Pro	synonymous	Exon 47 of 79	ENSP00000354923.3
	DMD	ENST00000474231.5	TSL:5	c.-553C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 35	ENSP00000417123.1
	DMD	ENST00000359836.5	TSL:5	c.-553C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 34	ENSP00000352894.1

Frequencies

GnomAD3 genomes AF: 0.000386 AC: 43 AN: 111293 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000621

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000513 AC: 94 AN: 183176 AF XY: 0.000532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000943

Gnomad NFE exome AF: 0.000844

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000748 AC: 821 AN: 1097715 Hom.: 1 Cov.: 31 AF XY: 0.000749 AC XY: 272 AN XY: 363087

African (AFR) AF: 0.0000379 AC: 1 AN: 26395

American (AMR) AF: 0.000483 AC: 17 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54136

European-Finnish (FIN) AF: 0.000766 AC: 31 AN: 40474

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4136

European-Non Finnish (NFE) AF: 0.000880 AC: 741 AN: 841697

Other (OTH) AF: 0.000608 AC: 28 AN: 46086

GnomAD4 genome AF: 0.000386 AC: 43 AN: 111343 Hom.: 0 Cov.: 22 AF XY: 0.000387 AC XY: 13 AN XY: 33557

African (AFR) AF: 0.0000653 AC: 2 AN: 30635

American (AMR) AF: 0.000674 AC: 7 AN: 10387

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3527

South Asian (SAS) AF: 0.00 AC: 0 AN: 2652

European-Finnish (FIN) AF: 0.000168 AC: 1 AN: 5948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000621 AC: 33 AN: 53131

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.000476 Hom.: 4

Bravo AF: 0.000389

EpiCase AF: 0.000873

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (1)
-	-	1	DMD-related disorder (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
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.54
DANN	Benign	0.26
PhyloP100		-0.014
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72466595; hg19: chrX-31947797;