10-93319879-G-A

Position:

• chr10-93319879-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_013451.4(MYOF):​c.5591C>T​(p.Ala1864Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,613,702 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: MYOF NM_013451.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01190567).
• BP6: Variant 10-93319879-G-A is Benign according to our data. Variant chr10-93319879-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3042231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOF	NM_013451.4	c.5591C>T	p.Ala1864Val	missense_variant	49/54	ENST00000359263.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOF	ENST00000359263.9	c.5591C>T	p.Ala1864Val	missense_variant	49/54	1	NM_013451.4	P1
MYOF	ENST00000358334.9	c.5552C>T	p.Ala1851Val	missense_variant	48/53	1
MYOF	ENST00000463743.5	c.*150C>T		3_prime_UTR_variant, NMD_transcript_variant	29/34	5

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 151964 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00245 AC: 612 AN: 249416 Hom.: 2 AF XY: 0.00251 AC XY: 340 AN XY: 135312

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00319 AC: 4661 AN: 1461620 Hom.: 12 Cov.: 31 AF XY: 0.00314 AC XY: 2285 AN XY: 727120

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152082 Hom.: 3 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74346

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000567

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00351 Hom.: 2

Bravo AF: 0.00199

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000534 AC: 2

ESP6500EA AF: 0.00376 AC: 31

ExAC AF: 0.00248 AC: 300

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00439

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

MYOF: BP4, BS2 -

MYOF-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.17	B;P
Vest4		0.42
MVP		0.82
MPC		0.26
ClinPred		0.044	T
GERP RS		5.8
Varity_R		0.28
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

Other links and lift over

dbSNP: rs146626145; hg19: chr10-95079636;