rs2276278

Positions:

• chr11-77161123-G-A
• chr11-77161123-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.1343+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 1,613,482 control chromosomes in the GnomAD database, including 6,123 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (971 hom., cov: 32)
  • Exomes 𝑓: 0.072 (5152 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002743
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.40

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-77161123-G-A is Benign according to our data. Variant chr11-77161123-G-A is described in ClinVar as [Benign]. Clinvar id is 43142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77161123-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1343+8G>A		splice_region_variant, intron_variant		ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1343+8G>A		splice_region_variant, intron_variant		1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.1343+8G>A		splice_region_variant, intron_variant		1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.1310+8G>A		splice_region_variant, intron_variant		1		ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0997 AC: 15169 AN: 152116 Hom.: 967 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.0966 AC: 24045 AN: 249004 Hom.: 1710 AF XY: 0.0916 AC XY: 12374 AN XY: 135094

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0853

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.0961

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0859

GnomAD4 exome AF: 0.0720 AC: 105237 AN: 1461248 Hom.: 5152 Cov.: 32 AF XY: 0.0719 AC XY: 52236 AN XY: 726870

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.0856

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.0938

Gnomad4 FIN exome AF: 0.0450

Gnomad4 NFE exome AF: 0.0573

Gnomad4 OTH exome AF: 0.0861

GnomAD4 genome AF: 0.0998 AC: 15186 AN: 152234 Hom.: 971 Cov.: 32 AF XY: 0.100 AC XY: 7449 AN XY: 74430

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.0859

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.0465

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.103

Alfa AF: 0.0665 Hom.: 480

Bravo AF: 0.111

Asia WGS AF: 0.186 AC: 646 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 13, 2008	c.1343+8G>A in intron 12 of MYO7A: This variant is not expected to have clinical significance because It has also been identified in 28% (2399/8596) of East Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs2276278). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 dominant nonsyndromic hearing loss 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.021
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs2276278; hg19: chr11-76872169; COSMIC: COSV68684024;