chr11-77205579-C-A

Position:

• chr11-77205579-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.5598C>A​(p.Leu1866Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,434 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1866L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.56

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-77205579-C-A is Benign according to our data. Variant chr11-77205579-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 43287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77205579-C-A is described in Lovd as [Benign]. Variant chr11-77205579-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00205 (312/152332) while in subpopulation NFE AF= 0.00332 (226/68020). AF 95% confidence interval is 0.00297. There are 0 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5598C>A	p.Leu1866Leu	synonymous_variant	40/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5598C>A	p.Leu1866Leu	synonymous_variant	40/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5484C>A	p.Leu1828Leu	synonymous_variant	40/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5451C>A	p.Leu1817Leu	synonymous_variant	41/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3024C>A	p.Leu1008Leu	synonymous_variant	20/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*196C>A		non_coding_transcript_exon_variant	23/32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*196C>A		3_prime_UTR_variant	23/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00220 AC: 545 AN: 247496 Hom.: 2 AF XY: 0.00215 AC XY: 289 AN XY: 134456

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000987

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.00633

GnomAD4 exome AF: 0.00301 AC: 4394 AN: 1461102 Hom.: 10 Cov.: 32 AF XY: 0.00285 AC XY: 2071 AN XY: 726796

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74478

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000628 Hom.: 4

Bravo AF: 0.00271

EpiCase AF: 0.00344

EpiControl AF: 0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYO7A: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
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	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2012	Leu1866Leu in exon 40 of MYO7A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 2.3% (82/3500) of Afric an American chromosomes in a broad population by the NHLBI Exome sequencing proj ect (http://evs.gs.washington.edu/EVS/; dbSNP rs111033504) and is reported as be nign in one publication (Jaijo 2009). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2018	- -

Autosomal dominant nonsyndromic hearing loss 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Usher syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.034
DANN	Benign	0.70

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: rs111033504; hg19: chr11-76916624;