X-32456676-T-C

Variant names:

• chrX-32456676-T-C
• rs6653872
• NM_004006.3:c.3433-1844A>G

Variant summary

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

The NM_004006.3(DMD):​c.3433-1844A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.17 (2037 hom., 4338 hem., cov: 19)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.829
• 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: 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 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.3433-1844A>G		intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.3421-1844A>G		intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.3409-1844A>G		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.3433-1844A>G		intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.3421-1844A>G		intron	N/A	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-91477A>G		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.171 AC: 18079 AN: 105829 Hom.: 2035 Cov.: 19

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.0520

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0914

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0673

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.157

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

GnomAD4 genome AF: 0.171 AC: 18106 AN: 105869 Hom.: 2037 Cov.: 19 AF XY: 0.150 AC XY: 4338 AN XY: 28947

African (AFR) AF: 0.394 AC: 11313 AN: 28709

American (AMR) AF: 0.144 AC: 1409 AN: 9771

Ashkenazi Jewish (ASJ) AF: 0.0914 AC: 237 AN: 2592

East Asian (EAS) AF: 0.160 AC: 527 AN: 3303

South Asian (SAS) AF: 0.132 AC: 316 AN: 2386

European-Finnish (FIN) AF: 0.0673 AC: 360 AN: 5346

Middle Eastern (MID) AF: 0.139 AC: 29 AN: 209

European-Non Finnish (NFE) AF: 0.0711 AC: 3661 AN: 51462

Other (OTH) AF: 0.154 AC: 219 AN: 1418

Alfa AF: 0.107 Hom.: 7870

Bravo AF: 0.192

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.18
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6653872; hg19: chrX-32474793;