X-32644134-G-C

Variant names:

• chrX-32644134-G-C
• rs1060502631
• NM_004006.3:c.1329C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004006.3(DMD):​c.1329C>G​(p.Ser443Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,089,248 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S443N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 missense, splice_region
• Scores: Splicing: ADA: 0.8647
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.96
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 12 uncertain in NM_004006.3
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.1329C>G	p.Ser443Arg	missense splice_region	Exon 11 of 79	NP_003997.2
	DMD	NM_004009.3		c.1317C>G	p.Ser439Arg	missense splice_region	Exon 11 of 79	NP_004000.1
	DMD	NM_000109.4		c.1305C>G	p.Ser435Arg	missense splice_region	Exon 11 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.1329C>G	p.Ser443Arg	missense splice_region	Exon 11 of 79	ENSP00000354923.3
	DMD	ENST00000288447.9	TSL:1	c.1305C>G	p.Ser435Arg	missense splice_region	Exon 11 of 18	ENSP00000288447.4
	DMD	ENST00000447523.1	TSL:1	c.247-70288C>G		intron	N/A	ENSP00000395904.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1089248 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 355462

African (AFR) AF: 0.00 AC: 0 AN: 26183

American (AMR) AF: 0.00 AC: 0 AN: 34853

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19179

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

South Asian (SAS) AF: 0.00 AC: 0 AN: 53288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4105

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 835513

Other (OTH) AF: 0.00 AC: 0 AN: 45797

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.61	T
PhyloP100		10
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.73
MutPred		0.34		Gain of MoRF binding (P = 0.0459)
MVP		0.61
MPC		0.091
ClinPred		0.97	D
GERP RS		5.7
gMVP		0.49
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Benign	0.57
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: rs1060502631; hg19: chrX-32662251; COSMIC: COSV55860328; COSMIC: COSV55860328;