rs16989902

Variant names:

• chrX-31875745-C-T
• rs16989902
• NM_004006.3:c.6913-372G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004006.3(DMD):​c.6913-372G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0087 in 112,151 control chromosomes in the GnomAD database, including 8 homozygotes. There are 275 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 0.0087 (8 hom., 275 hem., cov: 23)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.260
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0087 (976/112151) while in subpopulation AFR AF = 0.0263 (814/30932). AF 95% confidence interval is 0.0248. There are 8 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 976 XL,AD gene.

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.6913-372G>A		intron	N/A	NP_003997.2
	DMD	NM_004009.3		c.6901-372G>A		intron	N/A	NP_004000.1
	DMD	NM_000109.4		c.6889-372G>A		intron	N/A	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.6913-372G>A		intron	N/A	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.6901-372G>A		intron	N/A	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.2881-372G>A		intron	N/A	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.00863 AC: 967 AN: 112095 Hom.: 8 Cov.: 23

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00585

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00302

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000301

Gnomad OTH AF: 0.0113

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

GnomAD4 genome AF: 0.00870 AC: 976 AN: 112151 Hom.: 8 Cov.: 23 AF XY: 0.00801 AC XY: 275 AN XY: 34341

African (AFR) AF: 0.0263 AC: 814 AN: 30932

American (AMR) AF: 0.0107 AC: 113 AN: 10544

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 8 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00146 AC: 4 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000301 AC: 16 AN: 53232

Other (OTH) AF: 0.0112 AC: 17 AN: 1522

Alfa AF: 0.00648 Hom.: 20

Bravo AF: 0.0107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.49
DANN	Benign	0.71
PhyloP100		-0.26
PromoterAI		0.013	Neutral
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: rs16989902; hg19: chrX-31893862;