rs201203036

Positions:

chr11-77179055-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000260.4(MYO7A):c.2293C>A(p.Leu765Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000611 in 1,606,472 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00065 ( 1 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 3.44

Variant links:

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 links:

MYO7A (HGNC:):

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2231985).

BP6

Variant 11-77179055-C-A is Benign according to our data. Variant chr11-77179055-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43180.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.2293C>A	p.Leu765Met	missense_variant	20/49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.2293C>A	p.Leu765Met	missense_variant	20/49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.2293C>A	p.Leu765Met	missense_variant	20/49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.2260C>A	p.Leu754Met	missense_variant	21/50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000670577.1 linkuse as main transcript	n.133C>A		non_coding_transcript_exon_variant	3/32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000500

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000218

AC:

AN:

238042

Hom.:

AF XY:

0.000232

AC XY:

AN XY:

129420

show subpopulations

Gnomad AFR exome

AF:

0.0000706

Gnomad AMR exome

AF:

0.0000593

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.000429

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.000647

AC:

941

AN:

1454094

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

437

AN XY:

722516

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.000817

Gnomad4 OTH exome

AF:

0.000482

GnomAD4 genome

AF:

0.000263

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000144

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:

0.000500

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000548

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000590

AC:

ExAC

AF:

0.000225

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 09, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Leu765Met var iant in MYO7A has been previously identified by our laboratory in 5 individuals with hearing loss; however, a variant affecting the other copy of MYO7A was not identified in any of these individuals. This variant has also been reported in C linVar (Variation ID 43180) and has been identified in 56/121520 European chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg). Computational prediction tools and conservation analysis do not provide sup port for or against an impact the protein. In summary, while the clinical signif icance of the p.Leu765Met variant is uncertain, its frequency suggests it is mor e likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Autosomal recessive nonsyndromic hearing loss 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.2293C>A (p.L765M) alteration is located in exon 20 (coding exon 19) of the MYO7A gene. This alteration results from a C to A substitution at nucleotide position 2293, causing the leucine (L) at amino acid position 765 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 1B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Usher syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Autosomal dominant nonsyndromic hearing loss 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;T;.;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.053

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Uncertain

0.0016

MutationAssessor

Pathogenic

3.1

M;.;M;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.5

N;.;N;N;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.013

D;.;D;D;.

Sift4G

Uncertain

0.047

D;T;T;T;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.51

MVP

0.74

MPC

0.44

ClinPred

0.15

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over