X-32699292-A-G

Variant names:

• chrX-32699292-A-G
• rs1556930849
• NM_004006.3:c.651T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004006.3(DMD):​c.651T>C​(p.Asp217Asp) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000923 in 1,083,633 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.03154
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.70
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-32699292-A-G is Benign according to our data. Variant chrX-32699292-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 455921.Status of the report is criteria_provided_single_submitter, 1 stars.

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.651T>C	p.Asp217Asp	splice_region synonymous	Exon 8 of 79	NP_003997.2
	DMD	NM_004009.3		c.639T>C	p.Asp213Asp	splice_region synonymous	Exon 8 of 79	NP_004000.1
	DMD	NM_000109.4		c.627T>C	p.Asp209Asp	splice_region synonymous	Exon 8 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.651T>C	p.Asp217Asp	splice_region synonymous	Exon 8 of 79	ENSP00000354923.3
	DMD	ENST00000288447.9	TSL:1	c.627T>C	p.Asp209Asp	splice_region synonymous	Exon 8 of 18	ENSP00000288447.4
	DMD	ENST00000447523.1	TSL:1	c.246+124003T>C		intron	N/A	ENSP00000395904.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083633 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 349905

⚠️ 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: 26062

American (AMR) AF: 0.00 AC: 0 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19257

East Asian (EAS) AF: 0.00 AC: 0 AN: 30114

South Asian (SAS) AF: 0.00 AC: 0 AN: 53784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40459

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 829080

Other (OTH) AF: 0.00 AC: 0 AN: 45626

⚠️ 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 Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duchenne muscular dystrophy Benign:1

Feb 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.74
PhyloP100		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.032
dbscSNV1_RF	Benign	0.15
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: rs1556930849; hg19: chrX-32717409;