11-77147796-A-G

Position:

chr11-77147796-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000260.4(MYO7A):c.133-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,608,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.32

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 links:

MYO7A (HGNC:):

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02286402 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.2, offset of 21, new splice context is: aacactggatctctccgcAGaac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-77147796-A-G is Pathogenic according to our data. Variant chr11-77147796-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77147796-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.133-2A>G		splice_acceptor_variant, intron_variant		ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.133-2A>G	splice_acceptor_variant, intron_variant	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.133-2A>G	splice_acceptor_variant, intron_variant	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.100-2A>G	splice_acceptor_variant, intron_variant	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152058

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

GnomAD3 exomes

AF:

0.00000830

AC:

AN:

240926

Hom.:

AF XY:

0.00000762

AC XY:

AN XY:

131220

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000453

AC:

AN:

1456890

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

724194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 22, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness autosomal dominant 11 (MIM#601317), deafness autosomal recessive 2 (MIM#600060) and Usher syndrome, type 1B (MIM#276900). In addition, dominant negative is the suggested mechanism for missense variants in autosomal dominant inheritance (OMIM, PMID: 23383098). (I) 0108 - This gene is associated with both recessive and dominant disease. While the genotype-phenotype correlation is unestablished, missense variants causing autosomal dominant inheritance are rare and are not localised to a specific protein region (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant causes the skipping of the canonical acceptor splice site and activation of a cryptic splice site, shortening exon 4 by seven amino acids (p.Glu45_Gln51del) (PMID: 36240775). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple individuals with a second MYO7A variant with Usher syndrome and one individual with congenital bilateral sensorineural hearing loss without eye disease (PMID: 9171832, 27460420, 24199935, 36240775, 27145477). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000260.3(MYO7A):c.397C>A; p.(His133Asn)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1997	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2024	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27460420, 31479088, 33576163, 28472130, 31980526, 24199935, 22135276, 9171832, 36240775) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change affects an acceptor splice site in intron 3 of the MYO7A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). 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. Disruption of this splice site has been observed in individuals with clinical features of autosomal recessive Usher syndrome and non-syndromic deafness (PMID: 9171832, 22135276, 24199935, 27460420, 31479088). This variant is also known as IVS3nt-2a>g. ClinVar contains an entry for this variant (Variation ID: 555778). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 21, 2017

- -

Usher syndrome type 1B

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 12, 2020

- -

MYO7A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 12, 2020

Variant summary: MYO7A c.133-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict that the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-06 in 240926 control chromosomes (gnomAD). c.133-2A>G has been reported in the literature in multiple compound heterozygous individuals affected with MYO7A-Related Disorders (Usher syndrome type 1; e.g. Liu_1997, LeQuesneStabej_2012, Bonnet_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.97

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.94

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over