rs12420129

Variant names:

• chr11-77156089-C-T
• rs12420129
• NM_000260.4:c.468C>T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.468C>T​(p.Ile156Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,613,478 control chromosomes in the GnomAD database, including 1,402 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (209 hom., cov: 33)
  • Exomes 𝑓: 0.025 (1193 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.73

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 11-77156089-C-T is Benign according to our data. Variant chr11-77156089-C-T is described in ClinVar as [Benign]. Clinvar id is 43252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77156089-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.468C>T	p.Ile156Ile	splice_region_variant, synonymous_variant	Exon 5 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.468C>T	p.Ile156Ile	splice_region_variant, synonymous_variant	Exon 5 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.468C>T	p.Ile156Ile	splice_region_variant, synonymous_variant	Exon 5 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.435C>T	p.Ile145Ile	splice_region_variant, synonymous_variant	Exon 6 of 50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4686 AN: 152224 Hom.: 209 Cov.: 33

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0964

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0455 AC: 11310 AN: 248320 Hom.: 709 AF XY: 0.0388 AC XY: 5230 AN XY: 134754

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.0947

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0255 AC: 37188 AN: 1461136 Hom.: 1193 Cov.: 31 AF XY: 0.0242 AC XY: 17570 AN XY: 726798

Gnomad4 AFR exome AF: 0.00412

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0939

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0217

GnomAD4 genome AF: 0.0308 AC: 4690 AN: 152342 Hom.: 209 Cov.: 33 AF XY: 0.0354 AC XY: 2637 AN XY: 74494

Gnomad4 AFR AF: 0.00544

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0964

Gnomad4 NFE AF: 0.0216

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0279 Hom.: 92

Bravo AF: 0.0323

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0163

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Aug 10, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 11 Benign:2

Jan 16, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Usher syndrome type 1B Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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

LitVar

Other links and lift over

dbSNP: rs12420129; hg19: chr11-76867135;