rs111033416

chr11-77172818-G-Achr11-77172818-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000260.4(MYO7A):c.1868G>A(p.Arg623His) variant causes a missense change. The variant allele was found at a frequency of 0.000355 in 1,553,612 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R623L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (7 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 4.64

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000260.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.020085216).
• BP6: Variant 11-77172818-G-A is Benign according to our data. Variant chr11-77172818-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43162.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr11-77172818-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.1868G>A	p.Arg623His	missense_variant	16/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.1868G>A	p.Arg623His	missense_variant	16/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.1868G>A	p.Arg623His	missense_variant	16/49	1		P1
MYO7A	ENST00000409619.6	c.1835G>A	p.Arg612His	missense_variant	17/50	1
MYO7A	ENST00000669443.1	c.233G>A	p.Arg78His	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000716 AC: 113 AN: 157768 Hom.: 1 AF XY: 0.00101 AC XY: 84 AN XY: 83582

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00325

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000362 AC: 507 AN: 1401260 Hom.: 7 Cov.: 31 AF XY: 0.000466 AC XY: 322 AN XY: 691360

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000139

Gnomad4 ASJ exome AF: 0.00167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00309

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.000619

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74492

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000249

ExAC AF: 0.000549 AC: 57

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2020	Identified in a patient with retinitis pigmentosa in published literature who harbored a homozygous pathogenic variant in BBS2 which the authors considered to be causative (Watson et al., 2014); Identified in a patient with hearing loss in published literature; no specific details on the patient are provided (Iwasa et al., 2016); This variant is associated with the following publications: (PMID: 27911912, 25133751) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 22, 2015

p.Arg623His in exon 16 of MYO7A: This variant is not expected to have clinical significance because it has been identified in 0.325% (26/7988) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; rs111033416). Although this variant has been reported in the heterozygous state in one individual with retinal dystrophy (Watson 2014) and in three indiv iduals with hearing loss by our laboratory, the population frequency indicates t hat it is likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Oct 03, 2017

- -

Usher syndrome type 1B Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	1.4	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;.;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.62
MVP		0.90
MPC		0.51
ClinPred		0.083	T
GERP RS		4.8
Varity_R		0.44
gMVP		0.45

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: rs111033416; hg19: chr11-76883864;