rs397516333

Positions:

• chr11-77214625-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000260.4(MYO7A):​c.6577C>T​(p.Leu2193Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,432,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.81

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6577C>T	p.Leu2193Phe	missense_variant	49/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6577C>T	p.Leu2193Phe	missense_variant	49/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6457C>T	p.Leu2153Phe	missense_variant	49/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6430C>T	p.Leu2144Phe	missense_variant	50/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.4003C>T	p.Leu1335Phe	missense_variant	29/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*1149C>T		non_coding_transcript_exon_variant	32/32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*1149C>T		3_prime_UTR_variant	32/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432822 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709628

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 08, 2011

Variant classified as Uncertain Significance - Favor Pathogenic. The Leu2193Phe variant in MYO7A has not been reported in the literature nor previously identifi ed by our laboratory. This residue is conserved across species and computational analyses (PolyPhen2, SIFT) suggest that the Leu2193Phe variant may impact the p rotein. However, this information is not predictive enough to assume pathogenici ty. It should be noted that this lab has only sequenced the MYO7A in 20 Asian pr obands and no Asian healthy controls. In addition, healthy control information i s unavailable from either public databases or scientific literature, such that t he full spectrum of benign variation has not yet been defined for this populatio n. Future analysis could reveal that the Leu2193Phe variant is common in this po pulation and therefore unlikely to be pathogenic. However, the presence of this variant in combination with another pathogenic variant in this gene, increases t he likelihood that this variant is pathogenic if found to be in trans (on separa te copies of the gene). In summary, the clinical significance of this variant ca nnot be determined with certainty at this time; however, we would lean towards a more likely pathogenic role. -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.5	M;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.80
MutPred		0.57		Loss of stability (P = 0.0863);.;.;.;
MVP		0.85
MPC		0.48
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.90
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516333; hg19: chr11-76925670;