rs72468692

Variant names:

• chrX-32565806-T-C
• rs72468692
• NM_004006.3:c.1888A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-32565806-T-C
• chrX-32565806-T-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004006.3(DMD):​c.1888A>G​(p.Thr630Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,209,404 control chromosomes in the GnomAD database, including 2 homozygotes. There are 422 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T630K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., 59 hem., cov: 23)
  • Exomes 𝑓: 0.00092 (1 hom. 363 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.501
• 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: 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073586106).
• BP6: Variant X-32565806-T-C is Benign according to our data. Variant chrX-32565806-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 132 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.1888A>G	p.Thr630Ala	missense	Exon 16 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1876A>G	p.Thr626Ala	missense	Exon 16 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1864A>G	p.Thr622Ala	missense	Exon 16 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.1888A>G	p.Thr630Ala	missense	Exon 16 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1864A>G	p.Thr622Ala	missense	Exon 16 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.1876A>G	p.Thr626Ala	missense	Exon 16 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 132 AN: 111911 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0000325

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: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000639

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.00159 AC: 291 AN: 183238 AF XY: 0.00179

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: 0.0123

Gnomad NFE exome AF: 0.000905

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.000921 AC: 1011 AN: 1097439 Hom.: 1 Cov.: 30 AF XY: 0.00100 AC XY: 363 AN XY: 362829

African (AFR) AF: 0.0000379 AC: 1 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

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

South Asian (SAS) AF: 0.000499 AC: 27 AN: 54135

European-Finnish (FIN) AF: 0.0116 AC: 470 AN: 40522

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4133

European-Non Finnish (NFE) AF: 0.000547 AC: 460 AN: 841443

Other (OTH) AF: 0.00104 AC: 48 AN: 46059

GnomAD4 genome AF: 0.00118 AC: 132 AN: 111965 Hom.: 1 Cov.: 23 AF XY: 0.00173 AC XY: 59 AN XY: 34131

African (AFR) AF: 0.0000324 AC: 1 AN: 30858

American (AMR) AF: 0.00 AC: 0 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2711

European-Finnish (FIN) AF: 0.0156 AC: 95 AN: 6077

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000639 AC: 34 AN: 53183

Other (OTH) AF: 0.00132 AC: 2 AN: 1519

Alfa AF: 0.000458 Hom.: 17

Bravo AF: 0.000321

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00160 AC: 194

EpiCase AF: 0.000436

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (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	0.064
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.50
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.032
MVP		0.30
MPC		0.016
ClinPred		0.0045	T
GERP RS		-1.4
gMVP		0.055
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs72468692; hg19: chrX-32583923;