rs146517753

chrX-31478237-G-AchrX-31478237-G-CchrX-31478237-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004006.3(DMD):c.8806C>T(p.Leu2936Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000902 in 110,824 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2936I) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.60

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.8806C>T	p.Leu2936Phe	missense_variant	59/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.8806C>T	p.Leu2936Phe	missense_variant	59/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110824 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33018

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183173 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67645

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000902 AC: 1 AN: 110824 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33018

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

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 22, 2020

- -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1063912). This variant has not been reported in the literature in individuals affected with DMD-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2936 of the DMD protein (p.Leu2936Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;.;.;.;D;.;D;D;.
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;.;D;D;D;.;D;.;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D;.;D;D;D;.;D;.;D;D
Sift4G	Uncertain	0.055	T;T;T;T;T;D;D;D;D;T
Polyphen		0.93, 1.0, 0.92	.;.;P;D;P;.;D;.;.;P
Vest4		0.77, 0.73, 0.68, 0.69, 0.69, 0.75, 0.70, 0.71, 0.71
MVP		0.77
MPC		0.077
ClinPred		0.81	D
GERP RS		5.4
gMVP		0.48

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: rs146517753; hg19: chrX-31496354;