11-77179894-G-T

Variant names:

• chr11-77179894-G-T
• rs140559111
• NM_000260.4:c.2527G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000260.4(MYO7A):​c.2527G>T​(p.Val843Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,387,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.565

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15139139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.2527G>T	p.Val843Leu	missense_variant	Exon 21 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.2527G>T	p.Val843Leu	missense_variant	Exon 21 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.2527G>T	p.Val843Leu	missense_variant	Exon 21 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.2494G>T	p.Val832Leu	missense_variant	Exon 22 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.70G>T	p.Val24Leu	missense_variant	Exon 1 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.367G>T		non_coding_transcript_exon_variant	Exon 4 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000724 AC: 1 AN: 138042 Hom.: 0 AF XY: 0.0000134 AC XY: 1 AN XY: 74844

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: 0.000115

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1387354 Hom.: 0 Cov.: 31 AF XY: 0.00000292 AC XY: 2 AN XY: 684546

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: 0.0000126

Gnomad4 FIN exome AF: 0.0000254

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 27, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;T;.;.;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.85	T;T;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.79	N;.;N;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.87	N;.;N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.39	T;.;T;T;.;T
Sift4G	Benign	0.96	T;T;T;T;.;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.33
MutPred		0.54		Loss of catalytic residue at V843 (P = 0.0393);Loss of catalytic residue at V843 (P = 0.0393);Loss of catalytic residue at V843 (P = 0.0393);.;.;.;
MVP		0.79
MPC		0.084
ClinPred		0.15	T
GERP RS		5.4
Varity_R		0.10
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs140559111; hg19: chr11-76890940;