11-77180404-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000260.4(MYO7A):c.2617C>G(p.Arg873Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R873W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77180404-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.2617C>G	p.Arg873Gly	missense_variant	22/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.2617C>G	p.Arg873Gly	missense_variant	22/49	1	NM_000260.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245898 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134040

Gnomad AFR exome AF: 0.00

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: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459684 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725982

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000832 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T;.;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.6	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	D;.;D;D;.;D
REVEL	Pathogenic	0.78
Sift	Benign	0.095	T;.;T;T;.;T
Sift4G	Uncertain	0.033	D;D;D;D;.;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.87
MutPred		0.47		Loss of MoRF binding (P = 0.0095);Loss of MoRF binding (P = 0.0095);Loss of MoRF binding (P = 0.0095);.;.;.;
MVP		0.95
MPC		0.52
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.46
gMVP		0.55

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: rs200454015; hg19: chr11-76891450;