11-77214670-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_ModeratePP5

The NM_000260.4(MYO7A):c.6622C>T(p.Gln2208*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,584,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 7.53

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 3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00391 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PP5

Variant 11-77214670-C-T is Pathogenic according to our data. Variant chr11-77214670-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505014.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.6622C>T	p.Gln2208*	stop_gained	Exon 49 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.6622C>T	p.Gln2208*	stop_gained	Exon 49 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.6502C>T	p.Gln2168*	stop_gained	Exon 49 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.6475C>T	p.Gln2159*	stop_gained	Exon 50 of 50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 link	c.4048C>T	p.Gln1350*	stop_gained	Exon 29 of 29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 link	n.*1194C>T		non_coding_transcript_exon_variant	Exon 32 of 32			ENSP00000499323.1	A0A590UJ94
MYO7A	ENST00000670577.1 link	n.*1194C>T		3_prime_UTR_variant	Exon 32 of 32			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000983

AC:

AN:

203492

AF XY:

0.0000184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000342

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000558

AC:

AN:

1432668

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

709436

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32892

American (AMR)

AF:

0.0000249

AC:

AN:

40224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25612

East Asian (EAS)

AF:

0.00

AC:

AN:

38300

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000547

AC:

AN:

1097508

Other (OTH)

AF:

0.00

AC:

AN:

59438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00677733), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00000378

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 11

Pathogenic:1

Feb 28, 2023

King Laboratory, University of Washington

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This variant occurred in heterozygosity in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, this patient did not have known visual impairment (age 15y). This patient’s family has no other history of hearing loss. This variant is a nonsense that creates an early stop at position 2208 of the otherwise 2215 amino acid MYO7A protein. This stop is located within the final MYO7A exon and therefore extant truncated protein could interfere with the function of unaffected protein from the other allele, leading to a dominant inheritance pattern. As of January 2023, this variant has been reported to ClinVar as a variant of unknown significance and is not found on gnomAD. Based on the prediction that this variant leads to a truncated protein and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -

not specified

Uncertain:1

May 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gln2208X variant in MYO7A has not been previously reported in individuals with hearing loss. This variant was identified in 1/1250 Latino and 1/17806 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs747095250). Although this variant has been seen in the gener al population, its frequency is not high enough to rule out a pathogenic role. T his nonsense variant leads to a premature termination codon at amino acid positi on 2208. There are a total of 2216 amino acids in the MYO7A protein (NM_000260. 3). Therefore, this alteration occurs within the terminal 50 bases of the last e xon and is more likely to escape nonsense mediated decay (NMD) and result in a t runcated protein. Whether the truncation of 8 amino acids disrupts the function of the MYO7A protein is unknown. In summary, the clinical significance of the p. Gln2208X variant is uncertain. -

Usher syndrome type 1B

Uncertain:1

Mar 08, 2021

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 12, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation as the last 8 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

PhyloP100

7.5

Vest4

0.67

GERP RS

5.5

Mutation Taster

=13/187

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