rs377326213

Positions:

chr11-77182449-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000260.4(MYO7A):c.3134T>C(p.Ile1045Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,612,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 7.66

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a domain MyTH4 1 (size 236) in uniprot entity MYO7A_HUMAN there are 26 pathogenic changes around while only 4 benign (87%) in NM_000260.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.3134T>C	p.Ile1045Thr	missense_variant	25/49	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.3134T>C	p.Ile1045Thr	missense_variant	25/49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.3134T>C	p.Ile1045Thr	missense_variant	25/49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.3101T>C	p.Ile1034Thr	missense_variant	26/50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 linkuse as main transcript	c.677T>C	p.Ile226Thr	missense_variant	5/29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 linkuse as main transcript	n.974T>C		non_coding_transcript_exon_variant	8/32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

247390

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

134724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000224

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000110

AC:

160

AN:

1460826

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

726650

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000114

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MYO7A: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2023	Observed in homozygous state in a patient with Usher syndrome who also harbored a second homozygous variant in the MYO7A gene in the literature (Jaijo et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21311020, 25049390, 17361009, 35836572) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 23, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1045 of the MYO7A protein (p.Ile1045Thr). This variant is present in population databases (rs377326213, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 17361009). ClinVar contains an entry for this variant (Variation ID: 501914). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 22, 2017

- -

Usher syndrome type 1B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 20, 2020

- -

MYO7A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

The MYO7A c.3134T>C variant is predicted to result in the amino acid substitution p.Ile1045Thr. This variant has been reported in the homozygous state along with the MYO7A variant c.5507C>T (p.Leu1836Pro) also in the homozygous state in multiple individuals with Usher syndrome 1 (Jaijo et al. 2007. PubMed ID: 17361009; Table S3, Maltese et al. 2022. PubMed ID: 35836572). Karali M et al 2022. PubMed ID: 36460718). This variant has also been reported in a cohort study of retinal disease, but zygosity was not noted (Table S1, Karali. 2022. PubMed ID: 36460718). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, and possibly only when in cis with the variant c.5507C>T (p.Leu1836Pro), at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;T;.;.;.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.1

M;.;M;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.6

D;.;D;D;.;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.026

D;.;D;D;.;D

Sift4G

Uncertain

0.018

D;D;D;D;.;D

Polyphen

0.78

P;.;.;.;.;.

Vest4

0.73

MVP

0.97

MPC

0.16

ClinPred

0.32

GERP RS

5.5

Varity_R

0.37

gMVP

0.80

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