rs770149373

Variant names:

• chrX-32573845-A-G
• rs770149373
• NM_004006.3:c.1604T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_004006.3(DMD):​c.1604T>C​(p.Val535Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000368 in 1,085,974 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V535I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense, splice_region
• Scores: Splicing: ADA: 0.001136
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.52
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33693278).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AD geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1604T>C	p.Val535Ala	missense splice_region	Exon 14 of 79	NP_003997.2
	DMD	NM_004009.3		c.1592T>C	p.Val531Ala	missense splice_region	Exon 14 of 79	NP_004000.1
	DMD	NM_000109.4		c.1580T>C	p.Val527Ala	missense splice_region	Exon 14 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.1604T>C	p.Val535Ala	missense splice_region	Exon 14 of 79	ENSP00000354923.3
	DMD	ENST00000288447.9	TSL:1	c.1580T>C	p.Val527Ala	missense splice_region	Exon 14 of 18	ENSP00000288447.4
	DMD	ENST00000447523.1	TSL:1	c.248T>C	p.Val83Ala	missense splice_region	Exon 4 of 5	ENSP00000395904.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180752 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 4 AN: 1085974 Hom.: 0 Cov.: 29 AF XY: 0.00000569 AC XY: 2 AN XY: 351756

African (AFR) AF: 0.00 AC: 0 AN: 26192

American (AMR) AF: 0.00 AC: 0 AN: 35109

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19278

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.0000559 AC: 3 AN: 53658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831300

Other (OTH) AF: 0.0000219 AC: 1 AN: 45694

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.19	T
PhyloP100		3.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.11
Sift	Benign	0.36	T
Sift4G	Benign	0.15	T
Polyphen		0.15	B
Vest4		0.26
MutPred		0.41		Loss of catalytic residue at V535 (P = 0.0246)
MVP		0.92
MPC		0.066
ClinPred		0.25	T
GERP RS		4.0
gMVP		0.15
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.018
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: rs770149373; hg19: chrX-32591962;