rs757482211

Positions:

• chrX-32448568-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP3 BP6 BS2_Supporting

The NM_004006.3(DMD):​c.3674T>C​(p.Ile1225Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,095,920 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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). Synonymous variant affecting the same amino acid position (i.e. I1225I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.42

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 Likely_benign. Variant got -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• BP6: Variant X-32448568-A-G is Benign according to our data. Variant chrX-32448568-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575836.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.3674T>C	p.Ile1225Thr	missense_variant	27/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.3674T>C	p.Ile1225Thr	missense_variant	27/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000219 AC: 4 AN: 182270 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

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: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1095920 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 2 AN XY: 362420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000142

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

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.

Apr 15, 2020

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The p.I1225T variant (also known as c.3674T>C), located in coding exon 27 of the DMD gene, results from a T to C substitution at nucleotide position 3674. The isoleucine at codon 1225 is replaced by threonine, an amino acid with similar properties. Based on data from gnomAD, the C allele has an overall frequency of 0.0022% (4/182270) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0146% (4/27360) of Latino alleles. 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	.;N;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.19	.;T;.;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.91	.;P;.;.
Vest4		0.85
MutPred		0.69		.;.;Gain of disorder (P = 0.0248);Gain of disorder (P = 0.0248);
MVP		0.86
MPC		0.018
ClinPred		0.40	T
GERP RS		4.8
gMVP		0.18

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: rs757482211; hg19: chrX-32466685; COSMIC: COSV100820030;