11-77142783-C-G

Variant names:

• chr11-77142783-C-G
• rs35689081
• NM_000260.4:c.93C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000260.4(MYO7A):​c.93C>G​(p.Cys31Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C31C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.730
• Publications: 0 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

ACMG classification

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

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000260.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.93C>G	p.Cys31Trp	missense_variant	Exon 3 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.93C>G	p.Cys31Trp	missense_variant	Exon 3 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.93C>G	p.Cys31Trp	missense_variant	Exon 3 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.60C>G	p.Cys20Trp	missense_variant	Exon 4 of 50	1		ENSP00000386635.2
MYO7A	ENST00000660626.1	c.183C>G	p.Cys61Trp	missense_variant	Exon 2 of 2			ENSP00000499401.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458584 Hom.: 0 Cov.: 33 AF XY: 0.00000690 AC XY: 5 AN XY: 725088

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1110786

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.4	M;.;M;.
PhyloP100		-0.73
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.0	D;.;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.67
MutPred		0.45		Loss of catalytic residue at S33 (P = 0.0473);Loss of catalytic residue at S33 (P = 0.0473);Loss of catalytic residue at S33 (P = 0.0473);.;
MVP		0.79
MPC		0.54
ClinPred		1.0	D
GERP RS		-9.1
Varity_R		0.75
gMVP		0.75
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs35689081; hg19: chr11-76853829;