11-77205581-C-T

Position:

• chr11-77205581-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The ENST00000409709.9(MYO7A):​c.5600C>T​(p.Ala1867Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1867D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO7A ENST00000409709.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 13) in uniprot entity MYO7A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000409709.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5600C>T	p.Ala1867Val	missense_variant	40/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5600C>T	p.Ala1867Val	missense_variant	40/49	1	NM_000260.4	ENSP00000386331

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 26, 2015

The p.Ala1867Val variant in MYO7A has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, the clinical significance of the p.Ala1867Val va riant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.7	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.031	D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		0.38	B;.;.;.
Vest4		0.80
MutPred		0.76		Gain of MoRF binding (P = 0.0975);.;.;.;
MVP		0.94
MPC		0.24
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.72
gMVP		0.65

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: rs876657914; hg19: chr11-76916626;