rs797044517

Positions:

• chr11-77184684-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000260.4(MYO7A):​c.3472A>G​(p.Ile1158Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,447,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I1158I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.96

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.3472A>G	p.Ile1158Val	missense_variant	27/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.3472A>G	p.Ile1158Val	missense_variant	27/49	1	NM_000260.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000134 AC: 3 AN: 224370 Hom.: 0 AF XY: 0.0000165 AC XY: 2 AN XY: 121572

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: 0.0000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 25 AN: 1447156 Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11 AN XY: 718396

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: 0.0000226

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1158 of the MYO7A protein (p.Ile1158Val). 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. This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 179514). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO7A protein function with a negative predictive value of 95%. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 13, 2014

Variant classified as Uncertain Significance - Favor Benign. The Ile1158Val vari ant in MYO7A has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the frequency of th is variant. Computational analyses (amino acid biochemical properties, conservat ion, AlignGVGD, PolyPhen2, SIFT) suggest that the Ile1158Val variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, the clinical significance of this variant cannot be det ermined with certainty; however based the computational data, we would lean towa rds a more likely benign role. -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.;.;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.2	L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.67	N;.;N;N;.;N
REVEL	Uncertain	0.45
Sift	Benign	0.34	T;.;T;T;.;T
Sift4G	Benign	0.28	T;T;T;T;.;T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.37
MutPred		0.69		Loss of catalytic residue at L1163 (P = 0.062);.;Loss of catalytic residue at L1163 (P = 0.062);.;.;.;
MVP		0.82
MPC		0.42
ClinPred		0.61	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.25

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: rs797044517; hg19: chr11-76895729;