rs111033230

Variant names:

• chr11-77213940-C-T
• rs111033230
• NM_000260.4:c.6519C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.6519C>T​(p.Asn2173Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,090 control chromosomes in the GnomAD database, including 166 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 0.012 (12 hom., cov: 34)
  • Exomes 𝑓: 0.013 (154 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.52
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 11-77213940-C-T is Benign according to our data. Variant chr11-77213940-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43331.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1805/152384) while in subpopulation NFE AF = 0.014 (955/68036). AF 95% confidence interval is 0.0133. There are 12 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6519C>T	p.Asn2173Asn	synonymous_variant	Exon 48 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6519C>T	p.Asn2173Asn	synonymous_variant	Exon 48 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6399C>T	p.Asn2133Asn	synonymous_variant	Exon 48 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6372C>T	p.Asn2124Asn	synonymous_variant	Exon 49 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3945C>T	p.Asn1315Asn	synonymous_variant	Exon 28 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*1091C>T		non_coding_transcript_exon_variant	Exon 31 of 32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*1091C>T		3_prime_UTR_variant	Exon 31 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 152266 Hom.: 12 Cov.: 34

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0113 AC: 2812 AN: 249248 AF XY: 0.0116

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.00695

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0128 AC: 18744 AN: 1461706 Hom.: 154 Cov.: 38 AF XY: 0.0128 AC XY: 9310 AN XY: 727134

African (AFR) AF: 0.0119 AC: 397 AN: 33480

American (AMR) AF: 0.00729 AC: 326 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 813 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00995 AC: 858 AN: 86258

European-Finnish (FIN) AF: 0.00491 AC: 262 AN: 53396

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5768

European-Non Finnish (NFE) AF: 0.0136 AC: 15091 AN: 1111870

Other (OTH) AF: 0.0150 AC: 904 AN: 60374

GnomAD4 genome AF: 0.0118 AC: 1805 AN: 152384 Hom.: 12 Cov.: 34 AF XY: 0.0116 AC XY: 862 AN XY: 74518

African (AFR) AF: 0.0108 AC: 449 AN: 41608

American (AMR) AF: 0.00895 AC: 137 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4830

European-Finnish (FIN) AF: 0.00583 AC: 62 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 955 AN: 68036

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0147 Hom.: 14

Bravo AF: 0.0121

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0139

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO7A: BP4, BS1, BS2 -

Dec 28, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2013

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. -

Usher syndrome type 1 Benign:2

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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 1B Benign:1

Nov 27, 2019

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	-0.40
CADD	Benign	7.4
DANN	Benign	0.73
PhyloP100		2.5
Mutation Taster		=81/19	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: rs111033230; hg19: chr11-76924985; COSMIC: COSV108138281; COSMIC: COSV108138281;