rs184866544

Positions:

• chr11-77157346-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000260.4(MYO7A):​c.803A>G​(p.Lys268Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,612,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.966

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019367695).
• BP6: Variant 11-77157346-A-G is Benign according to our data. Variant chr11-77157346-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178477.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr11-77157346-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.803A>G	p.Lys268Arg	missense_variant	8/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.803A>G	p.Lys268Arg	missense_variant	8/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.803A>G	p.Lys268Arg	missense_variant	8/49	1		P1
MYO7A	ENST00000409619.6	c.770A>G	p.Lys257Arg	missense_variant	9/50	1

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 144 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000949 AC: 233 AN: 245618 Hom.: 0 AF XY: 0.000923 AC XY: 123 AN XY: 133242

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.000614

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.00161 AC: 2354 AN: 1459998 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 1109 AN XY: 725992

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000651

Gnomad4 ASJ exome AF: 0.000805

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.000995

GnomAD4 genome AF: 0.000945 AC: 144 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74488

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000869

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000512 AC: 2

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.000935 AC: 113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	Reported in published literature in an individual with Usher syndrome who was also heterozygous for a pathogenic variant in the USH2A gene, but was not present in an affected sibling (Bonnet et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 21569298, 25262649) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 17, 2015

p.Lys268Arg in exon 8 of MYO7A: This variant was reported in one individual with Usher syndrome type 2 but did not segregate in an affected sibling (Bonnet 2011 ). In addition, this variant was identified in 0.2% (100/53924) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs184866544). Furthermore, the lysine (Lys) residue at this position is not conserved in mammals and evolutionary distant species with two mammals, hor se and dolphin, having an arginine (Arg) at this position. In summary, this vari ant is not expected to have clinical significance based on lack of segregation w ith disease, the frequency of the variant in the general population, and conserv ation data. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MYO7A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2021

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	0.066
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.96	L;.;L;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.11	T;.;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.098
MVP		0.93
MPC		0.070
ClinPred		0.021	T
GERP RS		1.2
Varity_R		0.15
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs184866544; hg19: chr11-76868392;