rs115123584

chr11-77203215-T-Achr11-77203215-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000260.4(MYO7A):c.5324T>A(p.Ile1775Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000714 in 1,400,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. I1775T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.54

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 3 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, 8 uncertain in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2828092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.5324T>A	p.Ile1775Asn	missense_variant, splice_region_variant	38/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.5324T>A	p.Ile1775Asn	missense_variant, splice_region_variant	38/49	1	NM_000260.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 157736 Hom.: 0 AF XY: 0.0000237 AC XY: 2 AN XY: 84454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000396

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: 0.0000162

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000714 AC: 10 AN: 1400624 Hom.: 0 Cov.: 31 AF XY: 0.00000723 AC XY: 5 AN XY: 691268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000275

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: 0.00000832

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1775 of the MYO7A protein (p.Ile1775Asn). 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: 1220461). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In-silico analysis which includes splice predictors is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Uncertain	0.64	D;.;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.36	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.46
MutPred		0.52		Loss of stability (P = 0.037);.;.;.;
MVP		0.79
MPC		0.22
ClinPred		0.27	T
GERP RS		2.9
Varity_R		0.22
gMVP		0.52

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: rs115123584; hg19: chr11-76914260;