chr11-77192200-C-T

Variant names:

• chr11-77192200-C-T
• rs78996818
• NM_000260.4:c.4074C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.4074C>T​(p.Ser1358Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,614,052 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1358S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (31 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -5.40
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 11-77192200-C-T is Benign according to our data. Variant chr11-77192200-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43233.
• BP7: Synonymous conserved (PhyloP=-5.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00567 (864/152374) while in subpopulation AFR AF = 0.0082 (341/41594). AF 95% confidence interval is 0.00748. There are 5 homozygotes in GnomAd4. There are 419 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.4074C>T	p.Ser1358Ser	synonymous	Exon 31 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.4074C>T	p.Ser1358Ser	synonymous	Exon 31 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.4041C>T	p.Ser1347Ser	synonymous	Exon 32 of 50	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.4074C>T	p.Ser1358Ser	synonymous	Exon 31 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.4074C>T	p.Ser1358Ser	synonymous	Exon 31 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.4041C>T	p.Ser1347Ser	synonymous	Exon 32 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 864 AN: 152256 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00435 AC: 1085 AN: 249238 AF XY: 0.00464

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00459

Gnomad OTH exome AF: 0.00777

GnomAD4 exome AF: 0.00468 AC: 6844 AN: 1461678 Hom.: 31 Cov.: 32 AF XY: 0.00479 AC XY: 3482 AN XY: 727120

African (AFR) AF: 0.00783 AC: 262 AN: 33480

American (AMR) AF: 0.00508 AC: 227 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 314 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00446 AC: 385 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53368

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5768

European-Non Finnish (NFE) AF: 0.00463 AC: 5150 AN: 1111870

Other (OTH) AF: 0.00679 AC: 410 AN: 60374

GnomAD4 genome AF: 0.00567 AC: 864 AN: 152374 Hom.: 5 Cov.: 33 AF XY: 0.00562 AC XY: 419 AN XY: 74516

African (AFR) AF: 0.00820 AC: 341 AN: 41594

American (AMR) AF: 0.00693 AC: 106 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 336 AN: 68036

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00486 Hom.: 2

Bravo AF: 0.00657

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00563

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Jul 13, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser1358Ser in exon 31 of MYO7A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction and it occurs at an equal frequency in probands and the genera l population (Adato 1997, Janecke 1999, Jaijo 2006).

Mar 23, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 19, 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.

not provided Benign:3

Mar 30, 2019

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

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO7A: BP4, BP7, BS2

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Jan 13, 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 13, 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

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Usher syndrome type 1 Benign:1

Jan 13, 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.

Cohen syndrome Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.14
DANN	Benign	0.89
PhyloP100		-5.4
Mutation Taster		=87/13	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: rs78996818; hg19: chr11-76903245; COSMIC: COSV108246574; COSMIC: COSV108246574;