chrX-32645018-T-G

Variant names:

• chrX-32645018-T-G
• rs1800266
• NM_004006.3:c.1095A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004006.3(DMD):​c.1095A>C​(p.Gln365His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,209,990 control chromosomes in the GnomAD database, including 3 homozygotes. There are 223 hemizygotes in GnomAD. In-silico tool predicts 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. Q365R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00052 (3 hom. 212 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 2.14
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03573519).
• BP6: Variant X-32645018-T-G is Benign according to our data. Variant chrX-32645018-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282487.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000519 (570/1098142) while in subpopulation MID AF = 0.00604 (25/4137). AF 95% confidence interval is 0.0042. There are 3 homozygotes in GnomAdExome4. There are 212 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 38 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.1095A>C	p.Gln365His	missense	Exon 10 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1083A>C	p.Gln361His	missense	Exon 10 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1071A>C	p.Gln357His	missense	Exon 10 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.1095A>C	p.Gln365His	missense	Exon 10 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1071A>C	p.Gln357His	missense	Exon 10 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-71172A>C		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.000340 AC: 38 AN: 111848 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

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: 0.000620

Gnomad OTH AF: 0.000664

GnomAD2 exomes AF: 0.000529 AC: 97 AN: 183391 AF XY: 0.000693

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.000267

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000647

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.000519 AC: 570 AN: 1098142 Hom.: 3 Cov.: 31 AF XY: 0.000583 AC XY: 212 AN XY: 363538

African (AFR) AF: 0.0000379 AC: 1 AN: 26399

American (AMR) AF: 0.0000568 AC: 2 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00194 AC: 105 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00604 AC: 25 AN: 4137

European-Non Finnish (NFE) AF: 0.000477 AC: 402 AN: 842067

Other (OTH) AF: 0.000716 AC: 33 AN: 46095

GnomAD4 genome AF: 0.000340 AC: 38 AN: 111848 Hom.: 0 Cov.: 23 AF XY: 0.000323 AC XY: 11 AN XY: 34008

African (AFR) AF: 0.0000975 AC: 3 AN: 30779

American (AMR) AF: 0.0000956 AC: 1 AN: 10465

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000620 AC: 33 AN: 53187

Other (OTH) AF: 0.000664 AC: 1 AN: 1506

Alfa AF: 0.000543 Hom.: 27

Bravo AF: 0.000416

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.00125

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Duchenne muscular dystrophy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.67	T
PhyloP100		2.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.55		Loss of stability (P = 0.1213)
MVP		0.76
MPC		0.075
ClinPred		0.055	T
GERP RS		0.44
gMVP		0.56
Mutation Taster		=91/9	polymorphism (auto)

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: rs1800266; hg19: chrX-32663135; COSMIC: COSV55891577;