11-77160224-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000260.4(MYO7A):c.1142C>T(p.Thr381Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000949 in 1,581,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T381T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.19

Publications

7 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 1 benign, 16 uncertain in NM_000260.4

BP4

Computational evidence support a benign effect (MetaRNN=0.15099841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.1142C>T	p.Thr381Met	missense_variant	Exon 11 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.1142C>T	p.Thr381Met	missense_variant	Exon 11 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.1142C>T	p.Thr381Met	missense_variant	Exon 11 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.1109C>T	p.Thr370Met	missense_variant	Exon 12 of 50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

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:

0.000387

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000565

AC:

AN:

194800

AF XY:

0.0000382

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000705

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000840

AC:

AN:

1429154

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

707716

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32648

American (AMR)

AF:

0.00

AC:

AN:

40418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25556

East Asian (EAS)

AF:

0.000186

AC:

AN:

37622

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1096402

Other (OTH)

AF:

0.0000169

AC:

AN:

59192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

152170

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000584

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYO7A c.1142C>T (p.Thr381Met) results in a non-conservative amino acid change located in the motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 194800 control chromosomes (i.e., 11 heterozygotes), predominantly at a frequency of 0.0007 within the East Asian subpopulation in the gnomAD database. Although this frequency is not significantly higher than estimated for a pathogenic variant in MYO7A causing autosomal recessive Usher Syndrome (5.6e-05 vs 0.0061), the lack of complete phenotype data on the individuals within this cohort and this frequency does not allow conclusions about variant significance for either dominant or recessive association with disease. c.1142C>T has been reported in the literature predominantly in East Asian cohorts among several unrelated heterozygous individuals with hearing loss (e.g.,Li_2021), including as a de novo variant (e.g., Su_2009), and has also been identified in heterozygous affected individuals from the same family, suggesting the variant may segregate with disease (e.g., Wu_2013). Additionally, the variant has been reported in at least two compound heterozygous individuals with hearing loss, once in trans with a variant of uncertain significance (e.g., Yan_2016) and also in trans with a variant associated with autosomal dominant disease and recognized as likely pathogenic (e.g., Pan_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with Usher Syndrome or hearing loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33724713, 35640668, 19299023, 23451214, 27344577). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as VUS, and one submitter classified it as likely benign. Based on the evidence outlined above, a lack of experimental evidence on the variant effect, and ambiguity related to the exact inheritance pattern (dominant or recessive), the variant was classified as uncertain significance. -

Autosomal dominant nonsyndromic hearing loss 11

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

Uncertain:1

Jun 30, 2017

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 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;T;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.0

L;.;L;.

PhyloP100

3.2

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.8

D;.;D;D

REVEL

Uncertain

0.62

Sift

Benign

0.25

T;.;T;T

Sift4G

Benign

0.23

T;T;T;T

Polyphen

1.0

D;.;.;.

Vest4

0.80

MutPred

0.56

Loss of disorder (P = 0.0507);Loss of disorder (P = 0.0507);Loss of disorder (P = 0.0507);.;

MVP

0.93

MPC

0.44

ClinPred

0.43

GERP RS

5.1

Varity_R

0.25

gMVP

0.53

Mutation Taster

=0/100

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