rs748951363

Positions:

chr2-71511807-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001130987.2(DYSF):c.346G>A(p.Ala116Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000252 in 1,547,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

DYSF
NM_001130987.2 missense, splice_region

Scores

Splicing: ADA: 0.9962

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 8.15

Variant links:

Genes affected

DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

DYSF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant, splice_region_variant	5/56	ENST00000410020.8
DYSF	NM_003494.4 linkuse as main transcript	c.343G>A	p.Ala115Thr	missense_variant, splice_region_variant	5/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant, splice_region_variant	5/56	1	NM_001130987.2	A1	O75923-13
DYSF	ENST00000258104.8 linkuse as main transcript	c.343G>A	p.Ala115Thr	missense_variant, splice_region_variant	5/55	1	NM_003494.4	A1	O75923-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000192

AC:

AN:

156074

Hom.:

AF XY:

0.0000243

AC XY:

AN XY:

82160

show subpopulations

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:

0.0000332

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000251

AC:

AN:

1395586

Hom.:

Cov.:

AF XY:

0.0000131

AC XY:

AN XY:

688546

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000307

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

The c.343G>A (p.A115T) alteration is located in exon 5 (coding exon 5) of the DYSF gene. This alteration results from a G to A substitution at nucleotide position 343, causing the alanine (A) at amino acid position 115 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive limb-girdle muscular dystrophy type 2B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 15, 2020

- -

Qualitative or quantitative defects of dysferlin

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 115 of the DYSF protein (p.Ala115Thr). This variant is present in population databases (rs748951363, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 579035). 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"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;.;.;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.083

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.2

M;M;M;M;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0070

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.24

B;B;B;B;B;P;D;D;D;D;P

Vest4

0.61

MutPred

0.33

Gain of glycosylation at A115 (P = 0.0154);Gain of glycosylation at A115 (P = 0.0154);Gain of glycosylation at A115 (P = 0.0154);Gain of glycosylation at A115 (P = 0.0154);Gain of glycosylation at A115 (P = 0.0154);.;.;.;.;.;.;

MVP

0.81

MPC

0.44

ClinPred

0.44

GERP RS

4.5

Varity_R

0.63

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.82

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over