rs77625410

Positions:

• chr11-77202412-A-G

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.5156A>G​(p.Tyr1719Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,552,260 control chromosomes in the GnomAD database, including 770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (369 hom., cov: 32)
  • Exomes 𝑓: 0.012 (401 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 8.81

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]

MYO7A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002670139).
• BP6: Variant 11-77202412-A-G is Benign according to our data. Variant chr11-77202412-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 43274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77202412-A-G is described in Lovd as [Benign]. Variant chr11-77202412-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5156A>G	p.Tyr1719Cys	missense_variant	37/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5156A>G	p.Tyr1719Cys	missense_variant	37/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5042A>G	p.Tyr1681Cys	missense_variant	37/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5009A>G	p.Tyr1670Cys	missense_variant	38/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2582A>G	p.Tyr861Cys	missense_variant	17/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2996A>G		non_coding_transcript_exon_variant	20/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6829 AN: 152074 Hom.: 360 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00851

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0403

GnomAD3 exomes AF: 0.0161 AC: 2528 AN: 157078 Hom.: 82 AF XY: 0.0139 AC XY: 1160 AN XY: 83184

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00662

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0121 AC: 16918 AN: 1400068 Hom.: 401 Cov.: 31 AF XY: 0.0117 AC XY: 8103 AN XY: 690672

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.00716

Gnomad4 FIN exome AF: 0.00535

Gnomad4 NFE exome AF: 0.00894

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0451 AC: 6871 AN: 152192 Hom.: 369 Cov.: 32 AF XY: 0.0431 AC XY: 3206 AN XY: 74408

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00852

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.0399

Alfa AF: 0.0153 Hom.: 114

Bravo AF: 0.0499

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.111 AC: 448

ESP6500EA AF: 0.00896 AC: 74

ExAC AF: 0.0109 AC: 1117

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 1 Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Usher syndrome 1B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. 6 homozygotes in ExAC. -
Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 28, 2022

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.0	M;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.056	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.90	P;.;.;.
Vest4		0.83
MPC		0.48
ClinPred		0.016	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.46
gMVP		0.60

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: rs77625410; hg19: chr11-76913457;