rs56174006

Positions:

• chr11-77198514-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.4461C>T​(p.Asn1487Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0052 in 1,613,848 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).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (28 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: -1.98

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-77198514-C-T is Benign according to our data. Variant chr11-77198514-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43242.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2, Benign=5}. Variant chr11-77198514-C-T is described in Lovd as [Benign]. Variant chr11-77198514-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00587 (894/152314) while in subpopulation AFR AF= 0.00864 (359/41562). AF 95% confidence interval is 0.0079. There are 8 homozygotes in gnomad4. There are 404 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4461C>T	p.Asn1487Asn	synonymous_variant	34/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4461C>T	p.Asn1487Asn	synonymous_variant	34/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4461C>T	p.Asn1487Asn	synonymous_variant	34/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4428C>T	p.Asn1476Asn	synonymous_variant	35/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2004C>T	p.Asn668Asn	synonymous_variant	14/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2301C>T		non_coding_transcript_exon_variant	17/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 894 AN: 152196 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00866

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00604

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00394 AC: 980 AN: 248926 Hom.: 3 AF XY: 0.00403 AC XY: 545 AN XY: 135114

Gnomad AFR exome AF: 0.00990

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00513 AC: 7501 AN: 1461534 Hom.: 28 Cov.: 31 AF XY: 0.00507 AC XY: 3688 AN XY: 727056

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.00578

Gnomad4 OTH exome AF: 0.00472

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152314 Hom.: 8 Cov.: 33 AF XY: 0.00542 AC XY: 404 AN XY: 74478

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00604

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00519 Hom.: 1

Bravo AF: 0.00624

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2012	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2011	Asn1487Asn in exon 34 of MYO7A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located in a splice site and has been identified in 2% of cases. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MYO7A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Usher syndrome type 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.32
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs56174006; hg19: chr11-76909559;