rs748336386

Variant names:

• chrX-32348484-T-C
• rs748336386
• NM_004006.3:c.5370A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-32348484-T-C
• chrX-32348484-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004006.3(DMD):​c.5370A>G​(p.Ile1790Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,992 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. 13/19 in silico tools predict a benign outcome for this variant. 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. I1790V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.493
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13598347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.5370A>G	p.Ile1790Met	missense_variant	Exon 38 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.5370A>G	p.Ile1790Met	missense_variant	Exon 38 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000550 AC: 1 AN: 181775 AF XY: 0.00

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: 0.00000183 AC: 2 AN: 1093992 Hom.: 0 Cov.: 28 AF XY: 0.00000278 AC XY: 1 AN XY: 360226

African (AFR) AF: 0.00 AC: 0 AN: 26315

American (AMR) AF: 0.00 AC: 0 AN: 35067

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19298

East Asian (EAS) AF: 0.00 AC: 0 AN: 30068

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54019

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40237

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838946

Other (OTH) AF: 0.0000218 AC: 1 AN: 45922

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.27	.;T;.;.;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.78	T;.;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.49
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.57	.;N;.;N;N
REVEL	Benign	0.063
Sift	Uncertain	0.011	.;D;.;D;D
Sift4G	Benign	0.19	T;T;T;T;D
Polyphen		0.062	.;B;.;.;.
Vest4		0.29
MutPred		0.35		.;.;Gain of disorder (P = 0.074);Gain of disorder (P = 0.074);.;
MVP		0.69
MPC		0.045
ClinPred		0.21	T
GERP RS		2.9
PromoterAI		0.033	Neutral
gMVP		0.18
Mutation Taster		=94/6	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: rs748336386; hg19: chrX-32366601;