chr11-77190148-G-A

Variant names:

• chr11-77190148-G-A
• rs111033252
• NM_000260.4:c.3750+9G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000260.4(MYO7A):​c.3750+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,553,586 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (13 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: -0.217
• Publications: 1 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

ENSG00000296534 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-77190148-G-A is Benign according to our data. Variant chr11-77190148-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43222.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0019 (289/152336) while in subpopulation NFE AF = 0.00334 (227/68026). AF 95% confidence interval is 0.00298. There are 0 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.3750+9G>A		intron_variant	Intron 29 of 48	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3750+9G>A		intron_variant	Intron 29 of 48	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3750+9G>A		intron_variant	Intron 29 of 48	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3717+9G>A		intron_variant	Intron 30 of 49	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1293+9G>A		intron_variant	Intron 9 of 28	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1590+9G>A		intron_variant	Intron 12 of 31			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00186 AC: 293 AN: 157674 AF XY: 0.00192

Gnomad AFR exome AF: 0.000936

Gnomad AMR exome AF: 0.000288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00340 AC: 4767 AN: 1401250 Hom.: 13 Cov.: 32 AF XY: 0.00327 AC XY: 2263 AN XY: 691660

African (AFR) AF: 0.000597 AC: 19 AN: 31806

American (AMR) AF: 0.000421 AC: 15 AN: 35594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25000

East Asian (EAS) AF: 0.00 AC: 0 AN: 36290

South Asian (SAS) AF: 0.0000381 AC: 3 AN: 78804

European-Finnish (FIN) AF: 0.00283 AC: 138 AN: 48724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00410 AC: 4437 AN: 1081350

Other (OTH) AF: 0.00267 AC: 155 AN: 58104

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00180 AC XY: 134 AN XY: 74476

African (AFR) AF: 0.000625 AC: 26 AN: 41584

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00288 Hom.: 1

Bravo AF: 0.00183

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

3750+9G>A in intron 29 of MYO7A: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (31/8386) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS/; dbSNP rs111033252) -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Usher syndrome type 1B Benign:1

Apr 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.66
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs111033252; hg19: chr11-76901193;