X-31223056-C-A

Variant names:

• chrX-31223056-C-A
• rs200928985
• NM_004006.3:c.9352G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004006.3(DMD):​c.9352G>T​(p.Ala3118Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000348 in 1,207,203 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3118T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000035 (0 hom. 14 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 6.92
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3787263).
• BS2: High AC in GnomAdExome4 at 38 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.9352G>T	p.Ala3118Ser	missense	Exon 64 of 79	NP_003997.2
	DMD	NM_004009.3		c.9340G>T	p.Ala3114Ser	missense	Exon 64 of 79	NP_004000.1
	DMD	NM_000109.4		c.9328G>T	p.Ala3110Ser	missense	Exon 64 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.9352G>T	p.Ala3118Ser	missense	Exon 64 of 79	ENSP00000354923.3
	DMD	ENST00000378723.7	TSL:1	c.148G>T	p.Ala50Ser	missense	Exon 3 of 17	ENSP00000367997.3
	DMD	ENST00000361471.8	TSL:1	c.148G>T	p.Ala50Ser	missense	Exon 3 of 16	ENSP00000354464.4

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112027 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000436 AC: 8 AN: 183500 AF XY: 0.0000294

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: 0.0000976

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000347 AC: 38 AN: 1095176 Hom.: 0 Cov.: 29 AF XY: 0.0000388 AC XY: 14 AN XY: 360614

African (AFR) AF: 0.00 AC: 0 AN: 26339

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000441 AC: 37 AN: 839308

Other (OTH) AF: 0.00 AC: 0 AN: 46020

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 112027 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34187

African (AFR) AF: 0.00 AC: 0 AN: 30802

American (AMR) AF: 0.00 AC: 0 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3602

South Asian (SAS) AF: 0.00 AC: 0 AN: 2640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6103

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53251

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Duchenne muscular dystrophy (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)
-	1	-	not provided (1)
-	1	-	Primary familial dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.63	T
PhyloP100		6.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.24	T
Sift4G	Benign	0.21	T
Polyphen		0.33	B
Vest4		0.61
MutPred		0.51		Gain of disorder (P = 0.0687)
MVP		0.85
MPC		0.035
ClinPred		0.31	T
GERP RS		5.2
gMVP		0.33
Mutation Taster		=49/51	disease causing

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: rs200928985; hg19: chrX-31241173;