NM_000260.4:c.2293C>A

Variant names:

• chr11-77179055-C-A
• rs201203036
• NM_000260.4:c.2293C>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000260.4(MYO7A):​c.2293C>A​(p.Leu765Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000611 in 1,606,472 control chromosomes in the GnomAD database, including 1 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 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 3.44

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2231985).
• BP6: Variant 11-77179055-C-A is Benign according to our data. Variant chr11-77179055-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43180.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.2293C>A	p.Leu765Met	missense_variant	Exon 20 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.2293C>A	p.Leu765Met	missense_variant	Exon 20 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.2293C>A	p.Leu765Met	missense_variant	Exon 20 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.2260C>A	p.Leu754Met	missense_variant	Exon 21 of 50	1		ENSP00000386635.2
MYO7A	ENST00000670577.1	n.133C>A		non_coding_transcript_exon_variant	Exon 3 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000218 AC: 52 AN: 238042 Hom.: 0 AF XY: 0.000232 AC XY: 30 AN XY: 129420

Gnomad AFR exome AF: 0.0000706

Gnomad AMR exome AF: 0.0000593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.000429

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000647 AC: 941 AN: 1454094 Hom.: 1 Cov.: 30 AF XY: 0.000605 AC XY: 437 AN XY: 722516

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000817

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74518

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000548 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000590 AC: 5

ExAC AF: 0.000225 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Feb 01, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Aug 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Leu765Met var iant in MYO7A has been previously identified by our laboratory in 5 individuals with hearing loss; however, a variant affecting the other copy of MYO7A was not identified in any of these individuals. This variant has also been reported in C linVar (Variation ID 43180) and has been identified in 56/121520 European chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg). Computational prediction tools and conservation analysis do not provide sup port for or against an impact the protein. In summary, while the clinical signif icance of the p.Leu765Met variant is uncertain, its frequency suggests it is mor e likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

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. -

Inborn genetic diseases Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2293C>A (p.L765M) alteration is located in exon 20 (coding exon 19) of the MYO7A gene. This alteration results from a C to A substitution at nucleotide position 2293, causing the leucine (L) at amino acid position 765 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 1B Uncertain:1

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1 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. -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 11 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;.;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.053
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	0.0016	D
MutationAssessor	Pathogenic	3.1	M;.;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N;.;N;N;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.013	D;.;D;D;.
Sift4G	Uncertain	0.047	D;T;T;T;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.51
MVP		0.74
MPC		0.44
ClinPred		0.15	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.40

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: rs201203036; hg19: chr11-76890101;