11-77159449-C-G

Position:

• chr11-77159449-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000260.4(MYO7A):​c.1006C>G​(p.Arg336Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MYO7A NM_000260.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.84

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]

MYO7A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1006C>G	p.Arg336Gly	missense_variant, splice_region_variant	10/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1006C>G	p.Arg336Gly	missense_variant, splice_region_variant	10/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.1006C>G	p.Arg336Gly	missense_variant, splice_region_variant	10/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.973C>G	p.Arg325Gly	missense_variant, splice_region_variant	11/50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.096
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-0.26	N;.;N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;.;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.18	T;.;T;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.45	B;.;.;.
Vest4		0.89
MutPred		0.49		Gain of catalytic residue at R336 (P = 0.012);Gain of catalytic residue at R336 (P = 0.012);Gain of catalytic residue at R336 (P = 0.012);.;
MVP		0.91
MPC		0.12
ClinPred		0.77	D
GERP RS		3.9
Varity_R		0.27
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.73		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs369997614; hg19: chr11-76870495;