11-77157232-C-A

Variant names:

• chr11-77157232-C-A
• rs3737454
• NM_000260.4:c.736-47C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.736-47C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0758 in 1,491,962 control chromosomes in the GnomAD database, including 6,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1554 hom., cov: 33)
  • Exomes 𝑓: 0.071 (5028 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.29
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-77157232-C-A is Benign according to our data. Variant chr11-77157232-C-A is described in ClinVar as Benign. ClinVar VariationId is 255667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.736-47C>A		intron_variant	Intron 7 of 48	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.736-47C>A		intron_variant	Intron 7 of 48	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.736-47C>A		intron_variant	Intron 7 of 48	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.703-47C>A		intron_variant	Intron 8 of 49	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17966 AN: 152136 Hom.: 1549 Cov.: 33

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0463

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.0966 AC: 18633 AN: 192972 AF XY: 0.0916

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.0999

Gnomad EAS exome AF: 0.264

Gnomad FIN exome AF: 0.0440

Gnomad NFE exome AF: 0.0511

Gnomad OTH exome AF: 0.0921

GnomAD4 exome AF: 0.0710 AC: 95129 AN: 1339708 Hom.: 5028 Cov.: 21 AF XY: 0.0708 AC XY: 47276 AN XY: 668034

African (AFR) AF: 0.238 AC: 7142 AN: 29990

American (AMR) AF: 0.136 AC: 5121 AN: 37774

Ashkenazi Jewish (ASJ) AF: 0.0987 AC: 2466 AN: 24986

East Asian (EAS) AF: 0.280 AC: 10427 AN: 37212

South Asian (SAS) AF: 0.0920 AC: 7379 AN: 80174

European-Finnish (FIN) AF: 0.0451 AC: 2311 AN: 51230

Middle Eastern (MID) AF: 0.105 AC: 584 AN: 5570

European-Non Finnish (NFE) AF: 0.0537 AC: 54613 AN: 1016328

Other (OTH) AF: 0.0901 AC: 5086 AN: 56444

GnomAD4 genome AF: 0.118 AC: 18001 AN: 152254 Hom.: 1554 Cov.: 33 AF XY: 0.118 AC XY: 8807 AN XY: 74454

African (AFR) AF: 0.230 AC: 9564 AN: 41524

American (AMR) AF: 0.109 AC: 1676 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3472

East Asian (EAS) AF: 0.277 AC: 1436 AN: 5176

South Asian (SAS) AF: 0.101 AC: 487 AN: 4826

European-Finnish (FIN) AF: 0.0463 AC: 491 AN: 10612

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.0534 AC: 3631 AN: 68016

Other (OTH) AF: 0.112 AC: 236 AN: 2114

Alfa AF: 0.0829 Hom.: 654

Bravo AF: 0.131

Asia WGS AF: 0.192 AC: 665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.46
DANN	Benign	0.47
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3737454; hg19: chr11-76868278; COSMIC: COSV68684915;