rs554073390

Positions:

chr11-77184714-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000260.4(MYO7A):c.3502C>T(p.Arg1168Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,556,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1168P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 2.79

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 Pathogenic. Variant got 10 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-77184715-G-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.3502C>T	p.Arg1168Trp	missense_variant, splice_region_variant	27/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.3502C>T	p.Arg1168Trp	missense_variant, splice_region_variant	27/49	1	NM_000260.4	ENSP00000386331		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.0000504

AC:

AN:

118978

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:

0.000231

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000955

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000458

AC:

AN:

196306

Hom.:

AF XY:

0.0000654

AC XY:

AN XY:

107108

show subpopulations

Gnomad AFR exome

AF:

0.0000847

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000746

Gnomad FIN exome

AF:

0.0000722

Gnomad NFE exome

AF:

0.0000591

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000174

AC:

AN:

1437418

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

713574

show subpopulations

Gnomad4 AFR exome

AF:

0.0000910

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000196

Gnomad4 NFE exome

AF:

0.0000155

Gnomad4 OTH exome

AF:

0.0000505

GnomAD4 genome

AF:

0.0000504

AC:

AN:

119076

Hom.:

Cov.:

AF XY:

0.0000518

AC XY:

AN XY:

57902

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:

0.000231

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000955

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000693

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1168 of the MYO7A protein (p.Arg1168Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Usher syndrome and autosomal recessive deafness (PMID: 20052763, 21436283, 30303587, 33187236; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553405). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	MYO7A: PP3 -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Autosomal dominant nonsyndromic hearing loss 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 23, 2017

- -

MYO7A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2023

The MYO7A c.3502C>T variant is predicted to result in the amino acid substitution p.Arg1168Trp. This variant was reported in the heterozygous state without a second potentially causative variant in an individual with Usher syndrome (Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763), and in the homozygous state in two siblings from a consanguineous family with nonsyndromic hearing loss (Doll et al. 2020. PubMed ID: 33187236). This variant occurs at the penultimate nucleotide of exon 27, although in vitro studies found no effect on splicing (Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). This variant is reported in 0.0085% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-76895759-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

1.0

D;D;D;T;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.7

D;D;D;.;D

REVEL

Pathogenic

0.95

Sift

Benign

0.036

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.95

MutPred

0.91

Loss of phosphorylation at Y1172 (P = 0.1638);Loss of phosphorylation at Y1172 (P = 0.1638);.;.;.;

MVP

0.98

MPC

0.47

ClinPred

0.94

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.84

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