chrX-32463527-A-G

Variant names:

• chrX-32463527-A-G
• rs748123444
• NM_004006.3:c.3344T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_004006.3(DMD):​c.3344T>C​(p.Ile1115Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,201,721 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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. I1115L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom. 4 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 9.10
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41761753).
• BP6: Variant X-32463527-A-G is Benign according to our data. Variant chrX-32463527-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195878.
• BS2: High AC in GnomAdExome4 at 15 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.3344T>C	p.Ile1115Thr	missense	Exon 25 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.3332T>C	p.Ile1111Thr	missense	Exon 25 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.3320T>C	p.Ile1107Thr	missense	Exon 25 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.3344T>C	p.Ile1115Thr	missense	Exon 25 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.3332T>C	p.Ile1111Thr	missense	Exon 25 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-98328T>C		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111956 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 4 AN: 166459 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: 0.0000553

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 15 AN: 1089765 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 356369

African (AFR) AF: 0.00 AC: 0 AN: 26303

American (AMR) AF: 0.00 AC: 0 AN: 34540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19225

East Asian (EAS) AF: 0.00 AC: 0 AN: 29926

South Asian (SAS) AF: 0.00 AC: 0 AN: 52656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.0000167 AC: 14 AN: 837166

Other (OTH) AF: 0.0000218 AC: 1 AN: 45781

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111956 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34130

African (AFR) AF: 0.00 AC: 0 AN: 30749

American (AMR) AF: 0.00 AC: 0 AN: 10522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53256

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

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	-	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.88	T
PhyloP100		9.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.64	P
Vest4		0.33
MVP		0.60
MPC		0.018
ClinPred		0.35	T
GERP RS		5.4
gMVP		0.20
Mutation Taster		=88/12	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: rs748123444; hg19: chrX-32481644;