chrX-31479080-A-G

Variant names:

• chrX-31479080-A-G
• rs72466570
• NM_004006.3:c.8571T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004006.3(DMD):​c.8571T>C​(p.Thr2857Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,208,177 control chromosomes in the GnomAD database, including 3 homozygotes. There are 593 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2857T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., 44 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (1 hom. 549 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.151
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-31479080-A-G is Benign according to our data. Variant chrX-31479080-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.151 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0015 (167/111650) while in subpopulation NFE AF = 0.00229 (122/53163). AF 95% confidence interval is 0.00196. There are 2 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 167 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.8571T>C	p.Thr2857Thr	synonymous	Exon 58 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.8559T>C	p.Thr2853Thr	synonymous	Exon 58 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.8547T>C	p.Thr2849Thr	synonymous	Exon 58 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.8571T>C	p.Thr2857Thr	synonymous	Exon 58 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.8559T>C	p.Thr2853Thr	synonymous	Exon 58 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.4539T>C	p.Thr1513Thr	synonymous	Exon 30 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 167 AN: 111597 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000861

Gnomad ASJ AF: 0.00793

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00151 AC: 277 AN: 182856 AF XY: 0.00159

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000548

Gnomad ASJ exome AF: 0.00670

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00144 AC: 1579 AN: 1096527 Hom.: 1 Cov.: 29 AF XY: 0.00152 AC XY: 549 AN XY: 361949

African (AFR) AF: 0.000303 AC: 8 AN: 26371

American (AMR) AF: 0.000881 AC: 31 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00558 AC: 108 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54087

European-Finnish (FIN) AF: 0.000938 AC: 38 AN: 40500

Middle Eastern (MID) AF: 0.000969 AC: 4 AN: 4127

European-Non Finnish (NFE) AF: 0.00154 AC: 1293 AN: 840680

Other (OTH) AF: 0.00209 AC: 96 AN: 46023

GnomAD4 genome AF: 0.00150 AC: 167 AN: 111650 Hom.: 2 Cov.: 23 AF XY: 0.00130 AC XY: 44 AN XY: 33840

African (AFR) AF: 0.000358 AC: 11 AN: 30768

American (AMR) AF: 0.000860 AC: 9 AN: 10466

Ashkenazi Jewish (ASJ) AF: 0.00793 AC: 21 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2643

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5995

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

European-Non Finnish (NFE) AF: 0.00229 AC: 122 AN: 53163

Other (OTH) AF: 0.00197 AC: 3 AN: 1525

Alfa AF: 0.00253 Hom.: 37

Bravo AF: 0.00129

EpiCase AF: 0.00245

EpiControl AF: 0.00226

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	DMD-related disorder (1)
-	-	1	Duchenne muscular dystrophy (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	-0.55
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		0.15
Mutation Taster		=99/1	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: rs72466570; hg19: chrX-31497197;