X-32644279-C-T

Variant names:

• chrX-32644279-C-T
• rs148511512
• NM_004006.3:c.1184G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_004006.3(DMD):​c.1184G>A​(p.Arg395Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,209,024 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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. R395W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 55 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.82
• 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: 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014048845).
• BP6: Variant X-32644279-C-T is Benign according to our data. Variant chrX-32644279-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000099 (11/111146) while in subpopulation EAS AF = 0.00256 (9/3521). AF 95% confidence interval is 0.00133. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 11 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.1184G>A	p.Arg395Gln	missense	Exon 11 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1172G>A	p.Arg391Gln	missense	Exon 11 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1160G>A	p.Arg387Gln	missense	Exon 11 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.1184G>A	p.Arg395Gln	missense	Exon 11 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1160G>A	p.Arg387Gln	missense	Exon 11 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-70433G>A		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.0000990 AC: 11 AN: 111091 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: 0.00255

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 31 AN: 183073 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00224

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 175 AN: 1097878 Hom.: 0 Cov.: 30 AF XY: 0.000151 AC XY: 55 AN XY: 363308

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00543 AC: 164 AN: 30193

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841876

Other (OTH) AF: 0.000195 AC: 9 AN: 46081

GnomAD4 genome AF: 0.0000990 AC: 11 AN: 111146 Hom.: 0 Cov.: 23 AF XY: 0.0000898 AC XY: 3 AN XY: 33394

African (AFR) AF: 0.00 AC: 0 AN: 30592

American (AMR) AF: 0.00 AC: 0 AN: 10373

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00256 AC: 9 AN: 3521

South Asian (SAS) AF: 0.00 AC: 0 AN: 2628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5971

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53009

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000173 AC: 21

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Dystrophin deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.12
Sift	Benign	0.25	T
Sift4G	Benign	0.066	T
Polyphen		0.71	P
Vest4		0.31
MVP		0.63
MPC		0.016
ClinPred		0.053	T
GERP RS		4.0
gMVP		0.28
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148511512; hg19: chrX-32662396; COSMIC: COSV55881564; COSMIC: COSV55881564;