11-77142737-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):c.47T>C(p.Leu16Ser) variant causes a missense change. The variant allele was found at a frequency of 0.374 in 1,609,820 control chromosomes in the GnomAD database, including 120,171 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. L16L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.47 (19309 hom., cov: 32)
  • Exomes 𝑓: 0.36 (100862 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 4.72

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2303141E-6).
• BP6: Variant 11-77142737-T-C is Benign according to our data. Variant chr11-77142737-T-C is described in ClinVar as [Benign]. Clinvar id is 43258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77142737-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.47T>C	p.Leu16Ser	missense_variant	3/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.47T>C	p.Leu16Ser	missense_variant	3/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.47T>C	p.Leu16Ser	missense_variant	3/49	1		P1
MYO7A	ENST00000409619.6	c.14T>C	p.Leu5Ser	missense_variant	4/50	1
MYO7A	ENST00000660626.1	c.137T>C	p.Leu46Ser	missense_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.467 AC: 71017 AN: 151936 Hom.: 19262 Cov.: 32

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.473

GnomAD3 exomes AF: 0.393 AC: 95355 AN: 242580 Hom.: 20162 AF XY: 0.389 AC XY: 51164 AN XY: 131668

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.499

Gnomad SAS exome AF: 0.417

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.345

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.364 AC: 531187 AN: 1457764 Hom.: 100862 Cov.: 38 AF XY: 0.364 AC XY: 264100 AN XY: 724684

Gnomad4 AFR exome AF: 0.782

Gnomad4 AMR exome AF: 0.374

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.468 AC: 71116 AN: 152056 Hom.: 19309 Cov.: 32 AF XY: 0.464 AC XY: 34500 AN XY: 74312

Gnomad4 AFR AF: 0.761

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.472

Alfa AF: 0.371 Hom.: 17956

Bravo AF: 0.491

TwinsUK AF: 0.343 AC: 1272

ALSPAC AF: 0.322 AC: 1241

ESP6500AA AF: 0.724 AC: 3006

ESP6500EA AF: 0.342 AC: 2871

ExAC AF: 0.399 AC: 48127

Asia WGS AF: 0.460 AC: 1604 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Usher syndrome type 1 Benign:3

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Usher syndrome 1B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal recessive nonsyndromic hearing loss 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Benign	0.48
DEOGEN2	Benign	0.21	T;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.13	T;T;T;T
MetaRNN	Benign	0.0000012	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.2	N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	3.6	N;.;N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.082
MPC		0.12
ClinPred		0.030	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.11

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: rs1052030; hg19: chr11-76853783; COSMIC: COSV68684017;