rs781922871

Positions:

• chr11-77158331-C-G
• chr11-77158331-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000260.4(MYO7A):​c.904C>G​(p.Arg302Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R302H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77158332-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.904C>G	p.Arg302Gly	missense_variant	9/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.904C>G	p.Arg302Gly	missense_variant	9/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.904C>G	p.Arg302Gly	missense_variant	9/49	1		P1
MYO7A	ENST00000409619.6	c.871C>G	p.Arg291Gly	missense_variant	10/50	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248104 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134704

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460904 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726714

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 13, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 302 of the MYO7A protein (p.Arg302Gly). This variant is present in population databases (rs781922871, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. 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 expected to disrupt MYO7A protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.3	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.2	D;.;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;.;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.97	D;.;.;.
Vest4		0.76
MutPred		0.74		Gain of ubiquitination at K306 (P = 0.0716);Gain of ubiquitination at K306 (P = 0.0716);Gain of ubiquitination at K306 (P = 0.0716);.;
MVP		0.96
MPC		0.22
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.89
gMVP		0.73

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: rs781922871; hg19: chr11-76869377;