11-77208423-A-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.5857-7A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 1,593,946 control chromosomes in the GnomAD database, including 253,876 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 0.56 (24040 hom., cov: 33)
  • Exomes 𝑓: 0.56 (229836 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003007
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0280

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=-0.93).
• BP6: Variant 11-77208423-A-T is Benign according to our data. Variant chr11-77208423-A-T is described in ClinVar as [Benign]. Clinvar id is 43303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77208423-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.5857-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.5857-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85030 AN: 151642 Hom.: 24002 Cov.: 33

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.579

GnomAD3 exomes AF: 0.562 AC: 137338 AN: 244336 Hom.: 39040 AF XY: 0.553 AC XY: 73298 AN XY: 132486

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.674

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.505

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.569

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.561 AC: 808682 AN: 1442188 Hom.: 229836 Cov.: 31 AF XY: 0.557 AC XY: 399825 AN XY: 717988

Gnomad4 AFR exome AF: 0.519

Gnomad4 AMR exome AF: 0.670

Gnomad4 ASJ exome AF: 0.519

Gnomad4 EAS exome AF: 0.481

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.651

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.551

GnomAD4 genome AF: 0.561 AC: 85129 AN: 151758 Hom.: 24040 Cov.: 33 AF XY: 0.563 AC XY: 41715 AN XY: 74148

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.528

Gnomad4 EAS AF: 0.483

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.572

Gnomad4 OTH AF: 0.578

Alfa AF: 0.568 Hom.: 7962

Bravo AF: 0.561

Asia WGS AF: 0.444 AC: 1545 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 08, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -
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 13, 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	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Usher syndrome type 1 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 13, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	-0.93
Cadd	Benign	2.5
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0080
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: rs1320703; hg19: chr11-76919468; COSMIC: COSV68684425; COSMIC: COSV68684425;