11-77214596-C-T

Position:

• chr11-77214596-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000409709.9(MYO7A):​c.6559-11C>T 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 0.0214 in 1,556,648 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 32)
  • Exomes 𝑓: 0.022 (403 hom.)
• Consequence: MYO7A ENST00000409709.9 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002975
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0470

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=-0.54).
• BP6: Variant 11-77214596-C-T is Benign according to our data. Variant chr11-77214596-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77214596-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0152 (2320/152312) while in subpopulation SAS AF= 0.0251 (121/4822). AF 95% confidence interval is 0.0216. There are 19 homozygotes in gnomad4. There are 1125 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6559-11C>T		splice_polypyrimidine_tract_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.6559-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000260.4	ENSP00000386331

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2324 AN: 152194 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0225

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.0181 AC: 3287 AN: 181230 Hom.: 39 AF XY: 0.0192 AC XY: 1855 AN XY: 96400

Gnomad AFR exome AF: 0.00359

Gnomad AMR exome AF: 0.00820

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.000155

Gnomad SAS exome AF: 0.0254

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0221 AC: 31054 AN: 1404336 Hom.: 403 Cov.: 29 AF XY: 0.0222 AC XY: 15421 AN XY: 694742

Gnomad4 AFR exome AF: 0.00300

Gnomad4 AMR exome AF: 0.00885

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.0000810

Gnomad4 SAS exome AF: 0.0256

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0152 AC: 2320 AN: 152312 Hom.: 19 Cov.: 32 AF XY: 0.0151 AC XY: 1125 AN XY: 74470

Gnomad4 AFR AF: 0.00435

Gnomad4 AMR AF: 0.00934

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.0225

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0104 Hom.: 2

Bravo AF: 0.0136

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2014	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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2012	6559-11C>T in Intron 48 of MYO7A: This variant is not expected to have clinical significance because it has been identified in 1.9% (127/6834) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs34517202). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

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:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.4
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.24
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: rs34517202; hg19: chr11-76925641;