chr11-77162149-A-T

Position:

• chr11-77162149-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000409709.9(MYO7A):​c.1373A>T​(p.Asn458Ile) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N458K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A ENST00000409709.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000409709.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-77162149-A-T is Pathogenic according to our data. Variant chr11-77162149-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11863.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-77162149-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1373A>T	p.Asn458Ile	missense_variant	13/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1373A>T	p.Asn458Ile	missense_variant	13/49	1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000458637.6	c.1373A>T	p.Asn458Ile	missense_variant	13/49	1		ENSP00000392185	P1
MYO7A	ENST00000409619.6	c.1340A>T	p.Asn447Ile	missense_variant	14/50	1		ENSP00000386635

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 25, 2022	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. ClinVar contains an entry for this variant (Variation ID: 11863). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 15221449). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 458 of the MYO7A protein (p.Asn458Ile). -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal dominant nonsyndromic hearing loss 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;.;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.7	D;.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97	D;.;.;.
Vest4		0.98
MutPred		0.93		Gain of catalytic residue at N458 (P = 0.1043);Gain of catalytic residue at N458 (P = 0.1043);Gain of catalytic residue at N458 (P = 0.1043);.;
MVP		0.99
MPC		0.41
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.93

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: rs121965084; hg19: chr11-76873195;