rs111033195

Variant names:

• chr11-77190041-G-A
• rs111033195
• NM_000260.4:c.3652G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_000260.4(MYO7A):​c.3652G>A​(p.Gly1218Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,408,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1218A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.98
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296534 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-77190041-G-A is Pathogenic according to our data. Variant chr11-77190041-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43216.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.3652G>A	p.Gly1218Arg	missense_variant	Exon 29 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3652G>A	p.Gly1218Arg	missense_variant	Exon 29 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3652G>A	p.Gly1218Arg	missense_variant	Exon 29 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3619G>A	p.Gly1207Arg	missense_variant	Exon 30 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1195G>A	p.Gly399Arg	missense_variant	Exon 9 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1492G>A		non_coding_transcript_exon_variant	Exon 12 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000581 AC: 1 AN: 172088 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000497 AC: 7 AN: 1408596 Hom.: 0 Cov.: 32 AF XY: 0.00000287 AC XY: 2 AN XY: 695738

African (AFR) AF: 0.00 AC: 0 AN: 32168

American (AMR) AF: 0.00 AC: 0 AN: 37072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25272

East Asian (EAS) AF: 0.00 AC: 0 AN: 36754

South Asian (SAS) AF: 0.00 AC: 0 AN: 79768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5122

European-Non Finnish (NFE) AF: 0.00000645 AC: 7 AN: 1085098

Other (OTH) AF: 0.00 AC: 0 AN: 58322

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000855 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome Pathogenic:1

Apr 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYO7A c.3652G>A (p.Gly1218Arg) results in a non-conservative amino acid change located in the MyTH4 domain (IPR000857) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic exonic 3 acceptor site. Experimental evidence indicate the variant affects mRNA splicing (Aparisi_2013). The variant allele was found at a frequency of 5.8e-06 in 172088 control chromosomes (gnomAD). c.3652G>A has been reported in the literature in individuals affected with Usher Syndrome (Jaijo_2007, Baux_2017, Mansard_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23451239, 29196752, 17361009, 34948090, 33258288). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1218 of the MYO7A protein (p.Gly1218Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive deafness and/or Usher syndrome (PMID: 17361009, 29196752, 34948090). ClinVar contains an entry for this variant (Variation ID: 43216). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYO7A protein function with a negative predictive value of 95%. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 23451239). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Mar 01, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-0.35	N;N;.;.
PhyloP100		3.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.72	P;.;.;.
Vest4		0.55
MutPred		0.45		Gain of MoRF binding (P = 0.0707);Gain of MoRF binding (P = 0.0707);.;.;
MVP		0.96
MPC		0.19
ClinPred		0.72	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.59
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2
DS_AL_spliceai		0.33		Position offset: -21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111033195; hg19: chr11-76901086;