rs1132036

Positions:

• chr11-77213021-G-A

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.6424G>A​(p.Asp2142Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00542 in 1,580,324 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (217 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (173 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.37

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=0.002082765).
• BP6: Variant 11-77213021-G-A is Benign according to our data. Variant chr11-77213021-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6424G>A	p.Asp2142Asn	missense_variant	47/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6424G>A	p.Asp2142Asn	missense_variant	47/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6304G>A	p.Asp2102Asn	missense_variant	47/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6277G>A	p.Asp2093Asn	missense_variant	48/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3850G>A	p.Asp1284Asn	missense_variant	27/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*996G>A		non_coding_transcript_exon_variant	30/32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*996G>A		3_prime_UTR_variant	30/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4270 AN: 151964 Hom.: 214 Cov.: 31

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00709 AC: 1388 AN: 195658 Hom.: 62 AF XY: 0.00554 AC XY: 577 AN XY: 104216

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000366

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00544

GnomAD4 exome AF: 0.00298 AC: 4263 AN: 1428242 Hom.: 173 Cov.: 30 AF XY: 0.00264 AC XY: 1865 AN XY: 706864

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000257

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.0282 AC: 4295 AN: 152082 Hom.: 217 Cov.: 31 AF XY: 0.0283 AC XY: 2102 AN XY: 74330

Gnomad4 AFR AF: 0.0978

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00615 Hom.: 93

Bravo AF: 0.0321

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0791 AC: 312

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00756 AC: 907

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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 13, 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	0.17
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.040	N;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.42	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.33	B;.;.;.
Vest4		0.46
MVP		0.86
MPC		0.37
ClinPred		0.016	T
GERP RS		3.8
Varity_R		0.22
gMVP		0.69

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: rs1132036; hg19: chr11-76924066; COSMIC: COSV60020045; COSMIC: COSV60020045;