rs1556962392

Variant names:

• chrX-31875254-T-C
• rs1556962392
• NM_004006.3:c.7032A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_004021.3(DMD):​c.-349A>G 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 0.00000548 in 1,094,713 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 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:3
• Conservation: PhyloP100: -0.215
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.03).
• BP6: Variant X-31875254-T-C is Benign according to our data. Variant chrX-31875254-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526122.
• BS2: High AC in GnomAdExome4 at 6 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.7032A>G	p.Leu2344Leu	synonymous	Exon 48 of 79	NP_003997.2	P11532-1
	DMD	NM_004021.3		c.-349A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 35	NP_004012.2	P11532-14
	DMD	NM_004022.3		c.-349A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 34	NP_004013.2	P11532-15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.7032A>G	p.Leu2344Leu	synonymous	Exon 48 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000474231.5	TSL:5	c.-349A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 35	ENSP00000417123.1	A0A5H1ZRQ8
	DMD	ENST00000359836.5	TSL:5	c.-349A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 34	ENSP00000352894.1	A0A5H1ZRP9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1094713 Hom.: 0 Cov.: 31 AF XY: 0.00000555 AC XY: 2 AN XY: 360433

African (AFR) AF: 0.00 AC: 0 AN: 26344

American (AMR) AF: 0.00 AC: 0 AN: 34990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19294

East Asian (EAS) AF: 0.00 AC: 0 AN: 30136

South Asian (SAS) AF: 0.00 AC: 0 AN: 53431

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40417

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.00000595 AC: 5 AN: 840037

Other (OTH) AF: 0.0000218 AC: 1 AN: 45939

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (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	-0.78
CADD	Benign	2.2
DANN	Benign	0.77
PhyloP100		-0.21
PromoterAI		0.012	Neutral

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: rs1556962392; hg19: chrX-31893371;