rs111033183

Positions:

• chr11-77199555-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.4589C>T​(p.Ser1530Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,517,142 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (95 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.26

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002766192).
• BP6: Variant 11-77199555-C-T is Benign according to our data. Variant chr11-77199555-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77199555-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4589C>T	p.Ser1530Leu	missense_variant	35/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4589C>T	p.Ser1530Leu	missense_variant	35/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4569-94C>T		intron_variant		1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4536-94C>T		intron_variant		1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2112-94C>T		intron_variant		1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2429C>T		non_coding_transcript_exon_variant	18/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3344 AN: 152216 Hom.: 119 Cov.: 33

Gnomad AFR AF: 0.0755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00566 AC: 803 AN: 141834 Hom.: 23 AF XY: 0.00461 AC XY: 344 AN XY: 74548

Gnomad AFR exome AF: 0.0771

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000276

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000287

Gnomad OTH exome AF: 0.00402

GnomAD4 exome AF: 0.00232 AC: 3172 AN: 1364808 Hom.: 95 Cov.: 30 AF XY: 0.00207 AC XY: 1383 AN XY: 667262

Gnomad4 AFR exome AF: 0.0783

Gnomad4 AMR exome AF: 0.00531

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.0000632

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.00514

GnomAD4 genome AF: 0.0220 AC: 3352 AN: 152334 Hom.: 120 Cov.: 33 AF XY: 0.0214 AC XY: 1592 AN XY: 74496

Gnomad4 AFR AF: 0.0755

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00432 Hom.: 31

Bravo AF: 0.0244

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0853 AC: 118

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00435 AC: 504

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2010	This variant is not expected to have clinical significance because it has been i dentified in 3/17 (17.6%) Black probands in our lab, and as a homozygous variant in 2 individuals (Usher UMD), one of whom was homozygous for pathogenic MYO7A n onsense variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2016	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2014	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

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 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

- -

Usher syndrome type 1 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.33
Sift	Benign	0.34	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.42
MVP		0.82
MPC		0.075
ClinPred		0.0075	T
GERP RS		2.2
Varity_R		0.050
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111033183; hg19: chr11-76910600;