rs1469008607

Variant names:

• chrX-32389509-G-A
• rs1469008607
• NM_004006.3:c.4510C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32389509-G-A
• chrX-32389509-G-C

Variant summary

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

The NM_004006.3(DMD):​c.4510C>T​(p.His1504Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,225 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. H1504R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.77
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 2 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.4510C>T	p.His1504Tyr	missense	Exon 32 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.4498C>T	p.His1500Tyr	missense	Exon 32 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.4486C>T	p.His1496Tyr	missense	Exon 32 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.4510C>T	p.His1504Tyr	missense	Exon 32 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.4498C>T	p.His1500Tyr	missense	Exon 32 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.478C>T	p.His160Tyr	missense	Exon 4 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111865 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: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097360 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363020

African (AFR) AF: 0.00 AC: 0 AN: 26372

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30140

South Asian (SAS) AF: 0.00 AC: 0 AN: 54126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40497

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841471

Other (OTH) AF: 0.0000651 AC: 3 AN: 46059

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111865 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34057

African (AFR) AF: 0.00 AC: 0 AN: 30773

American (AMR) AF: 0.00 AC: 0 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6099

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53107

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	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	0.090
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.2	T
PhyloP100		7.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Benign	0.052	T
Sift4G	Benign	0.071	T
Polyphen		0.92	P
Vest4		0.50
MutPred		0.34		Loss of disorder (P = 0.0514)
MVP		0.44
MPC		0.065
ClinPred		0.79	D
GERP RS		5.6
gMVP		0.26
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1469008607; hg19: chrX-32407626;