rs797044518

chr11-77130635-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000260.4(MYO7A):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,216 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.42

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000260.4 (MYO7A) was described as [Likely_pathogenic] in ClinVar as 553231
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-77130635-A-G is Pathogenic according to our data. Variant chr11-77130635-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.1A>G	p.Met1?	start_lost	2/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.1A>G	p.Met1?	start_lost	2/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.1A>G	p.Met1?	start_lost	2/49	1		P1
MYO7A	ENST00000409619.6	c.-113A>G		5_prime_UTR_variant	2/50	1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247312 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134234

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: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461040 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726694

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

Gnomad4 AFR AF: 0.000121

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 03, 2023

Variant summary: MYO7A c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream in-frame initiation codon is at Met12. Another disruption of the initiator codon has been determined to be pathogenic in ClinVar (c.3G>A, p.Met1Ile). Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247312 control chromosomes. c.1A>G has been reported in the literature (Hanany_2020). This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31964843). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Usher syndrome type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Dec 05, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 27, 2023

This sequence change affects the initiator methionine of the MYO7A mRNA. The next in-frame methionine is located at codon 12. This variant is present in population databases (rs797044518, gnomAD 0.004%). Disruption of the initiator codon has been observed in individuals with clinical features of autosome recessive MYO7A-related conditions (PMID: 30459346; Invitae). ClinVar contains an entry for this variant (Variation ID: 179567). This variant disrupts a region of the MYO7A protein in which other variant(s) (p.Gly7Val ) have been determined to be pathogenic (PMID: 30303587). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2017

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.0099
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	-0.080	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-1.6	N;.;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0050	D;.;D
Sift4G	Benign	0.097	T;T;T
Polyphen		0.10	B;.;.
Vest4		0.88
MutPred		0.93		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.92
ClinPred		0.58	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044518; hg19: chr11-76841681;