rs141261536

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The ENST00000357033.9(DMD):ā€‹c.5548A>Gā€‹(p.Lys1850Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000232 in 1,207,733 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 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).

Frequency

Genomes: š‘“ 0.000081 ( 0 hom., 5 hem., cov: 22)
Exomes š‘“: 0.000017 ( 0 hom. 6 hem. )

Consequence

DMD
ENST00000357033.9 missense

Scores

3
4
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 6.95
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35542512).
BP6
Variant X-32345981-T-C is Benign according to our data. Variant chrX-32345981-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197077.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BS2
High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DMDNM_004006.3 linkuse as main transcriptc.5548A>G p.Lys1850Glu missense_variant 39/79 ENST00000357033.9 NP_003997.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkuse as main transcriptc.5548A>G p.Lys1850Glu missense_variant 39/791 NM_004006.3 ENSP00000354923 P4

Frequencies

GnomAD3 genomes
AF:
0.0000810
AC:
9
AN:
111089
Hom.:
0
Cov.:
22
AF XY:
0.000150
AC XY:
5
AN XY:
33327
show subpopulations
Gnomad AFR
AF:
0.000229
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000963
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:
0.00
Gnomad OTH
AF:
0.000668
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
182421
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
67237
show subpopulations
Gnomad AFR exome
AF:
0.000229
Gnomad AMR exome
AF:
0.00
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:
0.0000173
AC:
19
AN:
1096644
Hom.:
0
Cov.:
30
AF XY:
0.0000165
AC XY:
6
AN XY:
362660
show subpopulations
Gnomad4 AFR exome
AF:
0.000304
Gnomad4 AMR exome
AF:
0.0000285
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.000174
GnomAD4 genome
AF:
0.0000810
AC:
9
AN:
111089
Hom.:
0
Cov.:
22
AF XY:
0.000150
AC XY:
5
AN XY:
33327
show subpopulations
Gnomad4 AFR
AF:
0.000229
Gnomad4 AMR
AF:
0.0000963
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000668
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.000174
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 20, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 03, 2015- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 08, 2021The p.K1850E variant (also known as c.5548A>G), located in coding exon 39 of the DMD gene, results from an A to G substitution at nucleotide position 5548. The lysine at codon 1850 is replaced by glutamic acid, an amino acid with similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.002% (5/204076) total alleles studied, including one hemizygote. The highest observed frequency was 0.02% (4/18957) of African/African-American 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 04, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Benign
-0.034
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
.;T;.;.;T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
D;.;D;D;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Benign
0.36
T;T;T;T;T
MetaSVM
Benign
-0.80
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.32
.;N;.;N;D
REVEL
Uncertain
0.30
Sift
Benign
0.55
.;T;.;T;D
Sift4G
Benign
0.57
T;T;T;T;D
Polyphen
1.0
.;D;.;.;.
Vest4
0.74
MVP
0.86
MPC
0.045
ClinPred
0.30
T
GERP RS
5.8
gMVP
0.41

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: rs141261536; hg19: chrX-32364098; API