rs2276291

Positions:

• chr11-77207277-T-C

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.5743-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,592,366 control chromosomes in the GnomAD database, including 273,228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30386 hom., cov: 31)
  • Exomes 𝑓: 0.58 (242842 hom.)
• Consequence: MYO7A NM_000260.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001877
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.401

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-77207277-T-C is Benign according to our data. Variant chr11-77207277-T-C is described in ClinVar as [Benign]. Clinvar id is 43297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77207277-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.5743-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.5743-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95216 AN: 151836 Hom.: 30330 Cov.: 31

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.634

GnomAD3 exomes AF: 0.589 AC: 132727 AN: 225270 Hom.: 39793 AF XY: 0.577 AC XY: 70433 AN XY: 122052

Gnomad AFR exome AF: 0.738

Gnomad AMR exome AF: 0.692

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.508

Gnomad SAS exome AF: 0.437

Gnomad FIN exome AF: 0.656

Gnomad NFE exome AF: 0.585

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.577 AC: 831602 AN: 1440412 Hom.: 242842 Cov.: 30 AF XY: 0.573 AC XY: 409855 AN XY: 715568

Gnomad4 AFR exome AF: 0.737

Gnomad4 AMR exome AF: 0.688

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.483

Gnomad4 SAS exome AF: 0.444

Gnomad4 FIN exome AF: 0.656

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.574

GnomAD4 genome AF: 0.627 AC: 95342 AN: 151954 Hom.: 30386 Cov.: 31 AF XY: 0.628 AC XY: 46614 AN XY: 74268

Gnomad4 AFR AF: 0.733

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.488

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.658

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.632

Alfa AF: 0.597 Hom.: 7018

Bravo AF: 0.634

Asia WGS AF: 0.467 AC: 1625 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -

Autosomal recessive nonsyndromic hearing loss 2 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	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.51
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.020		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: rs2276291; hg19: chr11-76918322;