rs782063761

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP1_StrongPM3PP3

This summary comes from the ClinGen Evidence Repository: The c.1849T>C variant in MYO7A is a missense variant predicted to cause substitution of serine by proline at amino acid 617 (p.Ser617Pro). The highest population minor allele frequency in gnomAD v4 is 0.00009496 (8/84244 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with nonsyndromic hearing loss. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by parental testing (c.20G>T [p.Gly7Val], c.1258A>T [p.K420*], 2 PM3 points, PMIDs: 30303587, 33187236). One individual was homozygous for the variant (0.5 PM3 points, PMIDs: 27344577, 33671976) (PM3). The variant has been reported to segregate with nonsyndromic hearing loss in 7 affected family members from 3 families (PP1_Strong; PMIDs: 27344577, 30303587, 33187236, 33671976). This variant has also been detected in 1 individual with Usher syndrome, with a second variant c.4838delA (p.Asp1613ValfsTer32) without phase confirmation (PMIDs: 28041643, 32581362). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PM3, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024). As cases have been observed with both nonsyndromic hearing loss and Usher syndrome and genotype-phenotype correlation is currently unclear, individuals should be evaluated for both conditions. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6197628/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7U:1

Conservation

PhyloP100: 7.57

Publications

8 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 Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Usher syndrome type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss 11
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Likely_pathogenic. The variant received 7 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO7A	NM_000260.4	MANE Select	c.1849T>C	p.Ser617Pro	missense	Exon 16 of 49	NP_000251.3	Q13402-1
MYO7A	NM_001127180.2		c.1849T>C	p.Ser617Pro	missense	Exon 16 of 49	NP_001120652.1	Q13402-2
MYO7A	NM_001369365.1		c.1816T>C	p.Ser606Pro	missense	Exon 17 of 50	NP_001356294.1	Q13402-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.1849T>C	p.Ser617Pro	missense	Exon 16 of 49	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6	TSL:1	c.1849T>C	p.Ser617Pro	missense	Exon 16 of 49	ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6	TSL:1	c.1816T>C	p.Ser606Pro	missense	Exon 17 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152080

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:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

163212

AF XY:

0.0000230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000427

AC:

AN:

1405520

Hom.:

Cov.:

AF XY:

0.00000721

AC XY:

AN XY:

693888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31816

American (AMR)

AF:

0.00

AC:

AN:

36570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25238

East Asian (EAS)

AF:

0.00

AC:

AN:

36100

South Asian (SAS)

AF:

0.0000755

AC:

AN:

79432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082998

Other (OTH)

AF:

0.00

AC:

AN:

58286

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

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

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.:

ExAC

AF:

0.00000910

AC:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 2 (1)

Hearing loss, autosomal recessive (1)

Meniere disease (1)

Nonsyndromic genetic hearing loss (1)

not provided (1)

Usher syndrome (1)

Usher syndrome type 1 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

4.3

PhyloP100

7.6

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.95

MutPred

0.81

Loss of phosphorylation at S617 (P = 0.0546)

MVP

0.94

MPC

0.52

ClinPred

0.99

GERP RS

4.8

Varity_R

0.98

gMVP

0.92

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over