X-32849828-TA-TAAA

Variant names:

• chrX-32849828-T-TAA
• rs3834997
• NM_004006.3:c.94-10_94-9dupTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004006.3(DMD):​c.94-10_94-9dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 1,017,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000088 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• 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.

• BP6: Variant X-32849828-T-TAA is Benign according to our data. Variant chrX-32849828-T-TAA is described in ClinVar as Benign. ClinVar VariationId is 1166770.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.94-10_94-9dupTT		intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.82-10_82-9dupTT		intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.70-10_70-9dupTT		intron	N/A	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.94-9_94-8insTT		intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.70-9_70-8insTT		intron	N/A	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.82-9_82-8insTT		intron	N/A	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 178466 AF XY: 0.0000315

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000885 AC: 9 AN: 1017216 Hom.: 0 Cov.: 23 AF XY: 0.00000675 AC XY: 2 AN XY: 296404

⚠️ 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: 24983

American (AMR) AF: 0.00 AC: 0 AN: 34909

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18647

East Asian (EAS) AF: 0.00 AC: 0 AN: 29689

South Asian (SAS) AF: 0.00 AC: 0 AN: 52017

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40291

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3931

European-Non Finnish (NFE) AF: 0.0000117 AC: 9 AN: 769322

Other (OTH) AF: 0.00 AC: 0 AN: 43427

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00132524), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 596

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Duchenne muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0

Splicing

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

Other links and lift over

dbSNP: rs3834997; hg19: chrX-32867945;