rs1443021146

chrX-32501838-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_004006.3(DMD):c.2297T>C(p.Ile766Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,083,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. I766V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• BP6: Variant X-32501838-A-G is Benign according to our data. Variant chrX-32501838-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 455878.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.2297T>C	p.Ile766Thr	missense_variant	19/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.2297T>C	p.Ile766Thr	missense_variant	19/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000119 AC: 2 AN: 168258 Hom.: 0 AF XY: 0.0000183 AC XY: 1 AN XY: 54778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1083158 Hom.: 0 Cov.: 28 AF XY: 0.00000286 AC XY: 1 AN XY: 349600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 22, 2018

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2020

The p.I766T variant (also known as c.2297T>C), located in coding exon 19 of the DMD gene, results from a T to C substitution at nucleotide position 2297. The isoleucine at codon 766 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Duchenne muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	23
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.72
MutPred		0.48		.;.;Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);
MVP		0.83
MPC		0.066
ClinPred		0.53	D
GERP RS		5.3
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs1443021146; hg19: chrX-32519955;