rs948962

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000260.4(MYO7A):c.5860C>A(p.Leu1954Ile) variant causes a missense change. The variant allele was found at a frequency of 0.472 in 1,602,936 control chromosomes in the GnomAD database, including 184,200 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L1954L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.53 ( 22476 hom., cov: 33)

Exomes 𝑓: 0.47 ( 161724 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 5.96

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.922537E-6).

BP6

Variant 11-77208433-C-A is Benign according to our data. Variant chr11-77208433-C-A is described in ClinVar as [Benign]. Clinvar id is 43304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77208433-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.5860C>A	p.Leu1954Ile	missense_variant	43/49	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.5860C>A	p.Leu1954Ile	missense_variant	43/49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.5746C>A	p.Leu1916Ile	missense_variant	43/49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.5713C>A	p.Leu1905Ile	missense_variant	44/50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 linkuse as main transcript	c.3286C>A	p.Leu1096Ile	missense_variant	23/29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 linkuse as main transcript	n.*458C>A		non_coding_transcript_exon_variant	26/32			ENSP00000499323.1	A0A590UJ94
MYO7A	ENST00000670577.1 linkuse as main transcript	n.*458C>A		3_prime_UTR_variant	26/32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.532

AC:

80721

AN:

151740

Hom.:

22422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.696

Gnomad AMI

AF:

0.298

Gnomad AMR

AF:

0.512

Gnomad ASJ

AF:

0.451

Gnomad EAS

AF:

0.336

Gnomad SAS

AF:

0.311

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.468

Gnomad OTH

AF:

0.542

GnomAD3 exomes

AF:

0.474

AC:

116423

AN:

245742

Hom.:

28452

AF XY:

0.461

AC XY:

61477

AN XY:

133302

show subpopulations

Gnomad AFR exome

AF:

0.697

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.447

Gnomad EAS exome

AF:

0.355

Gnomad SAS exome

AF:

0.315

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.468

Gnomad OTH exome

AF:

0.470

GnomAD4 exome

AF:

0.466

AC:

676045

AN:

1451080

Hom.:

161724

Cov.:

AF XY:

0.461

AC XY:

332593

AN XY:

721950

show subpopulations

Gnomad4 AFR exome

AF:

0.704

Gnomad4 AMR exome

AF:

0.551

Gnomad4 ASJ exome

AF:

0.444

Gnomad4 EAS exome

AF:

0.324

Gnomad4 SAS exome

AF:

0.317

Gnomad4 FIN exome

AF:

0.561

Gnomad4 NFE exome

AF:

0.467

Gnomad4 OTH exome

AF:

0.468

GnomAD4 genome

AF:

0.532

AC:

80841

AN:

151856

Hom.:

22476

Cov.:

AF XY:

0.532

AC XY:

39442

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.696

Gnomad4 AMR

AF:

0.513

Gnomad4 ASJ

AF:

0.451

Gnomad4 EAS

AF:

0.336

Gnomad4 SAS

AF:

0.311

Gnomad4 FIN

AF:

0.569

Gnomad4 NFE

AF:

0.468

Gnomad4 OTH

AF:

0.540

Alfa

AF:

0.475

Hom.:

41056

Bravo

AF:

0.539

TwinsUK

AF:

0.478

AC:

1774

ALSPAC

AF:

0.461

AC:

1777

ESP6500AA

AF:

0.689

AC:

2851

ESP6500EA

AF:

0.481

AC:

4046

ExAC

AF:

0.468

AC:

56555

Asia WGS

AF:

0.362

AC:

1260

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -

Autosomal recessive nonsyndromic hearing loss 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal dominant nonsyndromic hearing loss 11

Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1

Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

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

0.037

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.21

T;.;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.45

T;T;T;T

MetaRNN

Benign

0.0000089

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.9

N;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

1.9

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Vest4

0.15

MPC

0.091

ClinPred

0.0016

GERP RS

4.3

Varity_R

0.097

gMVP

0.13

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

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