rs202245413

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000260.4(MYO7A):c.449G>A(p.Arg150Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,613,730 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R150R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 2 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 1.47

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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=0.13132462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.449G>A	p.Arg150Gln	missense_variant	5/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.449G>A	p.Arg150Gln	missense_variant	5/49	1	NM_000260.4		Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.449G>A	p.Arg150Gln	missense_variant	5/49	1		P1	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.416G>A	p.Arg139Gln	missense_variant	6/50	1			Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000309

AC:

AN:

248856

Hom.:

AF XY:

0.000267

AC XY:

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000541

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000553

AC:

808

AN:

1461514

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

390

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000679

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000361

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000680

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.000331

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with a MYO7A-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 31847883) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Arg150Gln var iant in MYO7A has been previously identified by our laboratory in 3 individuals with hearing loss, none of whom carried a variant on the other copy of MYO7A. Fu rthermore, one of these individuals had a variant in a different gene that was s ufficient to explain their hearing loss. This variant has also been identified i n 0.05% (65/126624) of European chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202245413). Although this vari ant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation ana lysis suggest that the variant may not impact the protein, though this informati on is not predictive enough to rule out pathogenicity. In summary, while the cli nical significance of the p.Arg150Gln variant is uncertain, these data suggest t hat it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -

Autosomal dominant nonsyndromic hearing loss 11

Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal recessive nonsyndromic hearing loss 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Usher syndrome type 1B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.50

T;T;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.039

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.45

N;.;N;.

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.25

Sift

Benign

0.32

T;.;T;T

Sift4G

Benign

0.65

T;T;T;T

Polyphen

0.026

B;.;.;.

Vest4

0.40

MVP

0.90

MPC

0.14

ClinPred

0.033

GERP RS

5.3

Varity_R

0.11

gMVP

0.53

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