11-77213940-C-T

Position:

• chr11-77213940-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 43331.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=7}. Variant chr11-77213940-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6519C>T	p.Asn2173Asn	synonymous_variant	48/49	ENST00000409709.9	NP_000251.3

Ensembl

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

GnomAD3 exomes AF: 0.0113 AC: 2812 AN: 249248 Hom.: 28 AF XY: 0.0116 AC XY: 1563 AN XY: 135220

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 SAS exome AF: 0.00990

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

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.00729

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00995

Gnomad4 FIN exome AF: 0.00491

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0150

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

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.00895

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00583

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.0156 Hom.: 13

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MYO7A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2013	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely 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 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

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.4
DANN	Benign	0.73

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: rs111033230; hg19: chr11-76924985;