Variant 10-93313030-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_013451.4(MYOF):c.5879G>A(p.Arg1960His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,608,930 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R1960C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 3 hom. )

Consequence

MYOF
NM_013451.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.81

Variant links:

Genes affected

MYOF (HGNC:3656): (myoferlin) Mutations in dysferlin, a protein associated with the plasma membrane, can cause muscle weakness that affects both proximal and distal muscles. The protein encoded by this gene is a type II membrane protein that is structurally similar to dysferlin. It is a member of the ferlin family and associates with both plasma and nuclear membranes. The protein contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. Two transcript variants encoding different isoforms have been found for this gene. Other possible variants have been detected, but their full-length nature has not been determined. [provided by RefSeq, Dec 2008]

MYOF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOF	NM_013451.4 linkuse as main transcript	c.5879G>A	p.Arg1960His	missense_variant	51/54	ENST00000359263.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOF	ENST00000359263.9 linkuse as main transcript	c.5879G>A	p.Arg1960His	missense_variant	51/54	1	NM_013451.4	P1	Q9NZM1-1
MYOF	ENST00000358334.9 linkuse as main transcript	c.5840G>A	p.Arg1947His	missense_variant	50/53	1			Q9NZM1-6
MYOF	ENST00000463743.5 linkuse as main transcript	c.*438G>A		3_prime_UTR_variant, NMD_transcript_variant	31/34	5

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000106

AC:

AN:

245212

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

133022

show subpopulations

Gnomad AFR exome

AF:

0.000389

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.000135

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.0000984

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

154

AN:

1456740

Hom.:

Cov.:

AF XY:

0.0000952

AC XY:

AN XY:

724454

show subpopulations

Gnomad4 AFR exome

AF:

0.000241

Gnomad4 AMR exome

AF:

0.0000683

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0000705

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000856

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000210

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000459

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.000524

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000179

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.5879G>A (p.R1960H) alteration is located in exon 51 (coding exon 51) of the MYOF gene. This alteration results from a G to A substitution at nucleotide position 5879, causing the arginine (R) at amino acid position 1960 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

-0.11

Eigen_PC

Benign

0.023

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.41

MutationTaster

Benign

0.95

N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.57

T;T

Polyphen

0.043

B;B

Vest4

0.18

MVP

0.84

MPC

0.19

ClinPred

0.071

GERP RS

5.3

Varity_R

0.19

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.44

Position offset: -1

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