rs1557362186

Variant names:

• chrX-32448524-G-T
• rs1557362186
• NM_004006.3:c.3718C>A

Variant summary

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

The NM_004006.3(DMD):​c.3718C>A​(p.Leu1240Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000128 in 1,095,943 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1240R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.10
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36002).
• BS2: High AC in GnomAdExome4 at 14 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.3718C>A	p.Leu1240Ile	missense	Exon 27 of 79	NP_003997.2
	DMD	NM_004009.3		c.3706C>A	p.Leu1236Ile	missense	Exon 27 of 79	NP_004000.1
	DMD	NM_000109.4		c.3694C>A	p.Leu1232Ile	missense	Exon 27 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.3718C>A	p.Leu1240Ile	missense	Exon 27 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.3706C>A	p.Leu1236Ile	missense	Exon 27 of 79	ENSP00000367948.2
	DMD	ENST00000682899.1		n.3925C>A		non_coding_transcript_exon	Exon 27 of 27

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1095943 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362495

African (AFR) AF: 0.00 AC: 0 AN: 26246

American (AMR) AF: 0.00 AC: 0 AN: 35169

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30138

South Asian (SAS) AF: 0.00 AC: 0 AN: 54092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 840456

Other (OTH) AF: 0.0000218 AC: 1 AN: 45942

GnomAD4 genome Cov.: 23

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	0.17
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.60	T
PhyloP100		5.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.23
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.57		Loss of ubiquitination at K1238 (P = 0.0563)
MVP		0.71
MPC		0.017
ClinPred		0.67	D
GERP RS		4.9
gMVP		0.12
Mutation Taster		=95/5	polymorphism

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: rs1557362186; hg19: chrX-32466641;