rs374576916

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4BP6

The NM_000260.4(MYO7A):c.5356T>A(p.Ser1786Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,601,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.57

Publications

0 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.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000260.4

BP4

Computational evidence support a benign effect (MetaRNN=0.27296865).

BP6

Variant 11-77204105-T-A is Benign according to our data. Variant chr11-77204105-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178491.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.5356T>A	p.Ser1786Thr	missense_variant	Exon 39 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.5356T>A	p.Ser1786Thr	missense_variant	Exon 39 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.5242T>A	p.Ser1748Thr	missense_variant	Exon 39 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.5209T>A	p.Ser1737Thr	missense_variant	Exon 40 of 50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 link	c.2782T>A	p.Ser928Thr	missense_variant	Exon 19 of 29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 link	n.3182T>A		non_coding_transcript_exon_variant	Exon 22 of 32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000746

AC:

AN:

227954

AF XY:

0.0000974

show subpopulations

Gnomad AFR exome

AF:

0.0000753

Gnomad AMR exome

AF:

0.000123

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000976

Gnomad OTH exome

AF:

0.000351

GnomAD4 exome

AF:

0.0000766

AC:

111

AN:

1449286

Hom.:

Cov.:

AF XY:

0.0000959

AC XY:

AN XY:

719674

show subpopulations

African (AFR)

AF:

0.000514

AC:

AN:

33080

American (AMR)

AF:

0.000116

AC:

AN:

43270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25892

East Asian (EAS)

AF:

0.00

AC:

AN:

38988

South Asian (SAS)

AF:

0.0000240

AC:

AN:

83460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52520

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000606

AC:

AN:

1106334

Other (OTH)

AF:

0.000133

AC:

AN:

59982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000112

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41554

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000135

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000992

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO7A: PM2, PP3 -

Inborn genetic diseases

Uncertain:1

Apr 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5356T>A (p.S1786T) alteration is located in exon 39 (coding exon 38) of the MYO7A gene. This alteration results from a T to A substitution at nucleotide position 5356, causing the serine (S) at amino acid position 1786 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Apr 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ser1786Thr in exon 39 of MYO7A: This variant is not expected to have clinical significance because it was identified by our laboratory in several unaffected i ndividuals from one Saudi Arabian family who were homozygous for the variant or compound heterozygous with another pathogenic variant in MYO7A. This variant has also been identified in 12/116102 of European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374576916). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.43

T;.;.;T

Eigen

Benign

-0.0099

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.0

M;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.0020

B;.;.;.

Vest4

0.68

MVP

0.91

MPC

0.10

ClinPred

0.066

GERP RS

3.6

Varity_R

0.49

gMVP

0.51

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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