rs782140421

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000260.4(MYO7A):c.3437G>A(p.Arg1146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,588,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1146W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 7.61

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
Usher syndrome type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant nonsyndromic hearing loss 11
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.3437G>A	p.Arg1146Gln	missense_variant	Exon 27 of 49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 link	c.3437G>A	p.Arg1146Gln	missense_variant	Exon 27 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.3437G>A	p.Arg1146Gln	missense_variant	Exon 27 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.3404G>A	p.Arg1135Gln	missense_variant	Exon 28 of 50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 link	c.980G>A	p.Arg327Gln	missense_variant	Exon 7 of 29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 link	n.1277G>A		non_coding_transcript_exon_variant	Exon 10 of 32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000191

AC:

AN:

209554

AF XY:

0.00000885

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000643

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000327

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1436052

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

711652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32970

American (AMR)

AF:

0.00

AC:

AN:

40932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25720

East Asian (EAS)

AF:

0.000207

AC:

AN:

38624

South Asian (SAS)

AF:

0.00

AC:

AN:

82602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51106

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000910

AC:

AN:

1098936

Other (OTH)

AF:

0.0000337

AC:

AN:

59414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Mar 27, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Usher syndrome type 1B

Uncertain:1

Aug 19, 2021

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Oct 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1146 of the MYO7A protein (p.Arg1146Gln). 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 Usher syndrome (PMID: 27460420). ClinVar contains an entry for this variant (Variation ID: 557475). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;T;.;.;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.55

D;D;D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.7

M;.;M;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.4

D;.;D;D;.;D

REVEL

Pathogenic

0.66

Sift

Benign

0.035

D;.;D;D;.;D

Sift4G

Uncertain

0.045

D;D;D;D;.;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.85

MutPred

0.28

Loss of phosphorylation at S1149 (P = 0.0682);.;Loss of phosphorylation at S1149 (P = 0.0682);.;.;.;

MVP

0.96

MPC

0.50

ClinPred

0.89

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.57

Mutation Taster

=1/99

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over