rs143925896

Variant names:

• chrX-31444533-G-A
• rs143925896
• NM_004006.3:c.9032C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-31444533-G-A
• chrX-31444533-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_004006.3(DMD):​c.9032C>T​(p.Pro3011Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,209,881 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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. P3011Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.09
• Publications: 2 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19876346).
• BP6: Variant X-31444533-G-A is Benign according to our data. Variant chrX-31444533-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198302.
• BS2: High AC in GnomAdExome4 at 10 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.9032C>T	p.Pro3011Leu	missense	Exon 60 of 79	NP_003997.2
	DMD	NM_004009.3		c.9020C>T	p.Pro3007Leu	missense	Exon 60 of 79	NP_004000.1
	DMD	NM_000109.4		c.9008C>T	p.Pro3003Leu	missense	Exon 60 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.9032C>T	p.Pro3011Leu	missense	Exon 60 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.9020C>T	p.Pro3007Leu	missense	Exon 60 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.5000C>T	p.Pro1667Leu	missense	Exon 32 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111868 Hom.: 0 Cov.: 22

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183310 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: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098013 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 2 AN XY: 363383

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30201

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000831 AC: 7 AN: 841940

Other (OTH) AF: 0.00 AC: 0 AN: 46088

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111868 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34042

African (AFR) AF: 0.00 AC: 0 AN: 30772

American (AMR) AF: 0.00 AC: 0 AN: 10476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2669

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

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

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53241

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.90	T
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.031
Sift	Benign	0.32	T
Sift4G	Benign	0.81	T
Polyphen		0.0060	B
Vest4		0.38
MVP		0.68
MPC		0.094
ClinPred		0.53	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.54
Mutation Taster		=83/17	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: rs143925896; hg19: chrX-31462650; COSMIC: COSV58957323;