rs16989352

Variant names:

• chrX-31121881-C-T
• rs16989352
• ENST00000378723.7:c.1860G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-31121881-C-T
• chrX-31121881-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004021.3(DMD):​c.3684G>A​(p.Ala1228Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,207,863 control chromosomes in the GnomAD database, including 19 homozygotes. There are 652 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., 218 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (8 hom. 434 hem.)
• Consequence: DMD NM_004021.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.166
• 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: 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

ENSG00000297249 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant X-31121881-C-T is Benign according to our data. Variant chrX-31121881-C-T is described in ClinVar as Benign. ClinVar VariationId is 226569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.166 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00729 (819/112293) while in subpopulation AFR AF = 0.0229 (709/30994). AF 95% confidence interval is 0.0215. There are 11 homozygotes in GnomAd4. There are 218 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 819 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004021.3. 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.*38G>A		3_prime_UTR	Exon 79 of 79	NP_003997.2	P11532-1
	DMD	NM_004021.3		c.3684G>A	p.Ala1228Ala	synonymous	Exon 35 of 35	NP_004012.2	P11532-14
	DMD	NM_004022.3		c.3645G>A	p.Ala1215Ala	synonymous	Exon 34 of 34	NP_004013.2	P11532-15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000378723.7	TSL:1	c.1860G>A	p.Ala620Ala	synonymous	Exon 17 of 17	ENSP00000367997.3	P11532-6
	DMD	ENST00000361471.8	TSL:1	c.1821G>A	p.Ala607Ala	synonymous	Exon 16 of 16	ENSP00000354464.4	P11532-5
	DMD	ENST00000378680.6	TSL:1	c.1530G>A	p.Ala510Ala	synonymous	Exon 13 of 13	ENSP00000367951.2	P11532-9

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 818 AN: 112241 Hom.: 11 Cov.: 23

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00360

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.00330

GnomAD2 exomes AF: 0.00261 AC: 477 AN: 182669 AF XY: 0.00183

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00235

Gnomad NFE exome AF: 0.000798

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00132 AC: 1447 AN: 1095570 Hom.: 8 Cov.: 28 AF XY: 0.00120 AC XY: 434 AN XY: 361368

African (AFR) AF: 0.0252 AC: 662 AN: 26322

American (AMR) AF: 0.00117 AC: 41 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19340

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54081

European-Finnish (FIN) AF: 0.00235 AC: 95 AN: 40391

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4131

European-Non Finnish (NFE) AF: 0.000621 AC: 522 AN: 839965

Other (OTH) AF: 0.00241 AC: 111 AN: 45982

GnomAD4 genome AF: 0.00729 AC: 819 AN: 112293 Hom.: 11 Cov.: 23 AF XY: 0.00631 AC XY: 218 AN XY: 34529

African (AFR) AF: 0.0229 AC: 709 AN: 30994

American (AMR) AF: 0.00254 AC: 27 AN: 10613

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2759

European-Finnish (FIN) AF: 0.00360 AC: 22 AN: 6117

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00105 AC: 56 AN: 53189

Other (OTH) AF: 0.00326 AC: 5 AN: 1533

Alfa AF: 0.00208 Hom.: 16

Bravo AF: 0.00872

EpiCase AF: 0.000928

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.5
DANN	Benign	0.83
PhyloP100		-0.17
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16989352; hg19: chrX-31139998;