rs1801188

Variant names:

• chrX-31679519-A-G
• rs1801188
• NM_004006.3:c.7728T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004006.3(DMD):​c.7728T>C​(p.Asn2576Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,209,378 control chromosomes in the GnomAD database, including 16,866 homozygotes. There are 77,011 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1216 hom., 5077 hem., cov: 23)
  • Exomes 𝑓: 0.20 (15650 hom. 71934 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.08
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-31679519-A-G is Benign according to our data. Variant chrX-31679519-A-G is described in ClinVar as Benign. ClinVar VariationId is 94776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 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.7728T>C	p.Asn2576Asn	synonymous	Exon 53 of 79	NP_003997.2
	DMD	NM_004009.3		c.7716T>C	p.Asn2572Asn	synonymous	Exon 53 of 79	NP_004000.1
	DMD	NM_000109.4		c.7704T>C	p.Asn2568Asn	synonymous	Exon 53 of 79	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.7728T>C	p.Asn2576Asn	synonymous	Exon 53 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.7716T>C	p.Asn2572Asn	synonymous	Exon 53 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.3696T>C	p.Asn1232Asn	synonymous	Exon 25 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 18031 AN: 111445 Hom.: 1217 Cov.: 23

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.235

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.170 AC: 31122 AN: 183044 AF XY: 0.173

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0828

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.348

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.199 AC: 218828 AN: 1097879 Hom.: 15650 Cov.: 31 AF XY: 0.198 AC XY: 71934 AN XY: 363295

African (AFR) AF: 0.0945 AC: 2495 AN: 26395

American (AMR) AF: 0.0902 AC: 3174 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 3489 AN: 19384

East Asian (EAS) AF: 0.399 AC: 12042 AN: 30199

South Asian (SAS) AF: 0.143 AC: 7736 AN: 54141

European-Finnish (FIN) AF: 0.131 AC: 5312 AN: 40477

Middle Eastern (MID) AF: 0.202 AC: 837 AN: 4137

European-Non Finnish (NFE) AF: 0.207 AC: 174517 AN: 841862

Other (OTH) AF: 0.200 AC: 9226 AN: 46080

GnomAD4 genome AF: 0.162 AC: 18039 AN: 111499 Hom.: 1216 Cov.: 23 AF XY: 0.151 AC XY: 5077 AN XY: 33721

African (AFR) AF: 0.0954 AC: 2935 AN: 30779

American (AMR) AF: 0.140 AC: 1471 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 461 AN: 2643

East Asian (EAS) AF: 0.360 AC: 1249 AN: 3469

South Asian (SAS) AF: 0.137 AC: 368 AN: 2682

European-Finnish (FIN) AF: 0.115 AC: 688 AN: 5985

Middle Eastern (MID) AF: 0.226 AC: 49 AN: 217

European-Non Finnish (NFE) AF: 0.197 AC: 10455 AN: 53001

Other (OTH) AF: 0.188 AC: 285 AN: 1516

Alfa AF: 0.191 Hom.: 4163

Bravo AF: 0.161

EpiCase AF: 0.203

EpiControl AF: 0.206

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Duchenne muscular dystrophy (3)
-	-	2	Dilated cardiomyopathy 3B (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.0
DANN	Benign	0.66
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1801188; hg19: chrX-31697636; COSMIC: COSV58894615;