rs878853236

Positions:

• chr11-77174789-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000409709.9(MYO7A):​c.1969C>T​(p.Arg657Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R657Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYO7A ENST00000409709.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.0220

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000409709.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-77174789-C-T is Pathogenic according to our data. Variant chr11-77174789-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77174789-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1969C>T	p.Arg657Trp	missense_variant	17/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1969C>T	p.Arg657Trp	missense_variant	17/49	1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000458637.6	c.1969C>T	p.Arg657Trp	missense_variant	17/49	1		ENSP00000392185	P1
MYO7A	ENST00000409619.6	c.1936C>T	p.Arg646Trp	missense_variant	18/50	1		ENSP00000386635
MYO7A	ENST00000409893.6	c.34C>T	p.Arg12Trp	missense_variant	1/11	5		ENSP00000386689

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000420 AC: 1 AN: 238114 Hom.: 0 AF XY: 0.00000772 AC XY: 1 AN XY: 129566

Gnomad AFR exome AF: 0.0000701

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455778 Hom.: 0 Cov.: 34 AF XY: 0.00000553 AC XY: 4 AN XY: 723550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000721

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16963483, 24105371, 36164746, 26309859, 33576794, 34148116, 33671976, 36460718, 26338283, 27460420) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 657 of the MYO7A protein (p.Arg657Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive non-syndromic deafness or Usher syndrome (PMID: 24105371, 26309859, 26338283, 27460420). ClinVar contains an entry for this variant (Variation ID: 242392). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

May 07, 2018

Recessive, congenital, profound NSHL -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 02, 2018

- -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.65	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.0	H;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.4	D;.;D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.99
MutPred		0.86		Loss of catalytic residue at R657 (P = 0.0645);Loss of catalytic residue at R657 (P = 0.0645);Loss of catalytic residue at R657 (P = 0.0645);.;.;
MVP		0.96
MPC		0.48
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.90
gMVP		0.87

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: rs878853236; hg19: chr11-76885835; COSMIC: COSV68686962;