chrX-32543196-G-T

Variant names:

• chrX-32543196-G-T
• rs7888911
• NM_004006.3:c.2168+1963C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004006.3(DMD):​c.2168+1963C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 111,168 control chromosomes in the GnomAD database, including 1,752 homozygotes. There are 4,606 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1752 hom., 4606 hem., cov: 23)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.982
• 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: 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

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.2168+1963C>A		intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2156+1963C>A		intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.2144+1963C>A		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.2168+1963C>A		intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.2144+1963C>A		intron	N/A	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.2156+1963C>A		intron	N/A	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.142 AC: 15769 AN: 111120 Hom.: 1754 Cov.: 23

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.0398

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.128

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.142 AC: 15787 AN: 111168 Hom.: 1752 Cov.: 23 AF XY: 0.138 AC XY: 4606 AN XY: 33434

African (AFR) AF: 0.370 AC: 11255 AN: 30430

American (AMR) AF: 0.159 AC: 1659 AN: 10432

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 45 AN: 2648

East Asian (EAS) AF: 0.195 AC: 684 AN: 3511

South Asian (SAS) AF: 0.0399 AC: 107 AN: 2680

European-Finnish (FIN) AF: 0.0857 AC: 511 AN: 5961

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.0251 AC: 1331 AN: 53089

Other (OTH) AF: 0.126 AC: 191 AN: 1515

Alfa AF: 0.0860 Hom.: 5300

Bravo AF: 0.167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.7
DANN	Benign	0.48
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

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: rs7888911; hg19: chrX-32561313;