rs727504594

Positions:

• chr11-77194372-C-G

Variant summary

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

The NM_000260.4(MYO7A):​c.4171C>G​(p.Leu1391Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.02

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.4171C>G	p.Leu1391Val	missense_variant	32/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4171C>G	p.Leu1391Val	missense_variant	32/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4171C>G	p.Leu1391Val	missense_variant	32/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4138C>G	p.Leu1380Val	missense_variant	33/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1714C>G	p.Leu572Val	missense_variant	12/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2011C>G		non_coding_transcript_exon_variant	15/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460040 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726100

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2013

The Leu1391Val in MYO7A has not been reported though frequency data from large p opulation studies is insufficient. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. Additional information is ne eded to fully assess the clinical significance of the Leu1391Val variant. -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;.;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.17	T;T;T;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.87	P;.;.;.
Vest4		0.74
MutPred		0.48		Loss of catalytic residue at L1391 (P = 0.1162);Loss of catalytic residue at L1391 (P = 0.1162);.;.;
MVP		0.79
MPC		0.095
ClinPred		0.87	D
GERP RS		4.3
Varity_R		0.14
gMVP		0.62

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: rs727504594; hg19: chr11-76905417;