chrX-32699141-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004006.3(DMD):ā€‹c.802T>Cā€‹(p.Leu268Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,208,727 control chromosomes in the GnomAD database, including 38 homozygotes. There are 960 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0035 ( 6 hom., 134 hem., cov: 23)
Exomes š‘“: 0.0022 ( 32 hom. 826 hem. )

Consequence

DMD
NM_004006.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.750
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant X-32699141-A-G is Benign according to our data. Variant chrX-32699141-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 94784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32699141-A-G is described in Lovd as [Benign]. Variant chrX-32699141-A-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.75 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00349 (390/111652) while in subpopulation AMR AF= 0.0291 (302/10393). AF 95% confidence interval is 0.0264. There are 6 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DMDNM_004006.3 linkuse as main transcriptc.802T>C p.Leu268Leu synonymous_variant 8/79 ENST00000357033.9 NP_003997.2 P11532

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkuse as main transcriptc.802T>C p.Leu268Leu synonymous_variant 8/791 NM_004006.3 ENSP00000354923.3 A0A075B6G3

Frequencies

GnomAD3 genomes
AF:
0.00350
AC:
391
AN:
111600
Hom.:
6
Cov.:
23
AF XY:
0.00396
AC XY:
134
AN XY:
33814
show subpopulations
Gnomad AFR
AF:
0.000682
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0292
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00817
Gnomad SAS
AF:
0.0101
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00663
GnomAD3 exomes
AF:
0.00830
AC:
1518
AN:
182897
Hom.:
20
AF XY:
0.00650
AC XY:
439
AN XY:
67587
show subpopulations
Gnomad AFR exome
AF:
0.000456
Gnomad AMR exome
AF:
0.0438
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00651
Gnomad SAS exome
AF:
0.00960
Gnomad FIN exome
AF:
0.0000626
Gnomad NFE exome
AF:
0.000110
Gnomad OTH exome
AF:
0.00666
GnomAD4 exome
AF:
0.00221
AC:
2429
AN:
1097075
Hom.:
32
Cov.:
29
AF XY:
0.00228
AC XY:
826
AN XY:
362717
show subpopulations
Gnomad4 AFR exome
AF:
0.000303
Gnomad4 AMR exome
AF:
0.0429
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00932
Gnomad4 SAS exome
AF:
0.00824
Gnomad4 FIN exome
AF:
0.000296
Gnomad4 NFE exome
AF:
0.0000547
Gnomad4 OTH exome
AF:
0.00271
GnomAD4 genome
AF:
0.00349
AC:
390
AN:
111652
Hom.:
6
Cov.:
23
AF XY:
0.00396
AC XY:
134
AN XY:
33876
show subpopulations
Gnomad4 AFR
AF:
0.000680
Gnomad4 AMR
AF:
0.0291
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00819
Gnomad4 SAS
AF:
0.0101
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000189
Gnomad4 OTH
AF:
0.00655
Alfa
AF:
0.00122
Hom.:
5
Bravo
AF:
0.00592
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 12, 2015p.Leu268Leu in exon 8 of DMD: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 4.5% (421/9271) of L atino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs1800264). -
Benign, criteria provided, single submitterclinical testingGeneDxApr 15, 2014This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 11, 2015- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 16, 2019- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsSep 12, 2017- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Aug 09, 2017- -
Dilated cardiomyopathy 3B Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 10, 2015This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Duchenne muscular dystrophy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
6.5
DANN
Benign
0.74

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1800264; hg19: chrX-32717258; COSMIC: COSV99919944; API