chrX-31836735-C-T

Variant names:

• chrX-31836735-C-T
• rs72466590
• NM_004006.3:c.7183G>A

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.7183G>A​(p.Ala2395Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,209,410 control chromosomes in the GnomAD database, including 4 homozygotes. There are 652 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 38 hem., cov: 23)
  • Exomes 𝑓: 0.0018 (4 hom. 614 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14 O:1
• Conservation: PhyloP100: 1.94
• 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=0.018843055).
• BP6: Variant X-31836735-C-T is Benign according to our data. Variant chrX-31836735-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94757.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00128 (144/112174) while in subpopulation NFE AF = 0.00218 (116/53229). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 144 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.7183G>A	p.Ala2395Thr	missense	Exon 49 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.7171G>A	p.Ala2391Thr	missense	Exon 49 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.7159G>A	p.Ala2387Thr	missense	Exon 49 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.7183G>A	p.Ala2395Thr	missense	Exon 49 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000471779.1	TSL:1	n.49G>A		non_coding_transcript_exon	Exon 1 of 3	ENSP00000417075.1	A0A0C4DH61
	DMD	ENST00000378677.6	TSL:5	c.7171G>A	p.Ala2391Thr	missense	Exon 49 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 144 AN: 112119 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000867 AC: 159 AN: 183371 AF XY: 0.000825

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00178 AC: 1957 AN: 1097236 Hom.: 4 Cov.: 30 AF XY: 0.00169 AC XY: 614 AN XY: 362654

African (AFR) AF: 0.000265 AC: 7 AN: 26386

American (AMR) AF: 0.000398 AC: 14 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30181

South Asian (SAS) AF: 0.0000924 AC: 5 AN: 54123

European-Finnish (FIN) AF: 0.000272 AC: 11 AN: 40505

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4134

European-Non Finnish (NFE) AF: 0.00219 AC: 1839 AN: 841270

Other (OTH) AF: 0.00167 AC: 77 AN: 46059

GnomAD4 genome AF: 0.00128 AC: 144 AN: 112174 Hom.: 0 Cov.: 23 AF XY: 0.00111 AC XY: 38 AN XY: 34344

African (AFR) AF: 0.000194 AC: 6 AN: 30949

American (AMR) AF: 0.00171 AC: 18 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.000371 AC: 1 AN: 2697

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00218 AC: 116 AN: 53229

Other (OTH) AF: 0.00130 AC: 2 AN: 1535

Alfa AF: 0.00146 Hom.: 67

Bravo AF: 0.00125

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.000733 AC: 89

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	4	not specified (5)
-	-	2	Duchenne muscular dystrophy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (1)
-	-	1	Hereditary skeletal muscle disorder (1)
-	-	-	Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.15
Sift	Benign	0.47	T
Sift4G	Benign	0.71	T
Polyphen		0.14	B
Vest4		0.17
MVP		0.84
MPC		0.016
ClinPred		0.012	T
GERP RS		4.8
gMVP		0.17
Mutation Taster		=274/26	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: rs72466590; hg19: chrX-31854852;