rs121965082

Positions:

• chr11-77166162-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000260.4(MYO7A):​c.1797G>A​(p.Met599Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M599T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.84

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-77166162-G-A is Pathogenic according to our data. Variant chr11-77166162-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11856.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-77166162-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.1797G>A	p.Met599Ile	missense_variant, splice_region_variant	15/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.1797G>A	p.Met599Ile	missense_variant, splice_region_variant	15/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.1797G>A	p.Met599Ile	missense_variant, splice_region_variant	15/49	1		P1
MYO7A	ENST00000409619.6	c.1764G>A	p.Met588Ile	missense_variant, splice_region_variant	16/50	1
MYO7A	ENST00000669443.1	c.108G>A	p.Met36Ile	missense_variant, splice_region_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 2001

- -

Usher syndrome type 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.1	L;.;L;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D;.;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.032	D;.;D;D
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.97	D;.;.;.
Vest4		0.63
MutPred		0.32		Loss of disorder (P = 0.0808);Loss of disorder (P = 0.0808);Loss of disorder (P = 0.0808);.;
MVP		0.86
MPC		0.41
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.56
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: 9

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

Publications

LitVar

Other links and lift over

dbSNP: rs121965082; hg19: chr11-76877208;