rs1555111106

Variant names:

• chr11-77213896-A-G
• rs1555111106
• NM_000260.4:c.6475A>G

Variant summary

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

The NM_000260.4(MYO7A):​c.6475A>G​(p.Asn2159Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • 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: 7.11

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.6475A>G	p.Asn2159Asp	missense_variant	Exon 48 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.6475A>G	p.Asn2159Asp	missense_variant	Exon 48 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.6355A>G	p.Asn2119Asp	missense_variant	Exon 48 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.6328A>G	p.Asn2110Asp	missense_variant	Exon 49 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3901A>G	p.Asn1301Asp	missense_variant	Exon 28 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*1047A>G		non_coding_transcript_exon_variant	Exon 31 of 32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*1047A>G		3_prime_UTR_variant	Exon 31 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461694 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn2159Asp variant in MYO7A variant has not been previously reported in in dividuals with hearing loss or Usher syndrome. Data from large population studie s are insufficient to assess the frequency of this variant in the general popula tion. Computational prediction tools and conservation analyses suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, the clinical significance of the p.As n2159Asp variant is uncertain. -

Usher syndrome type 1B Uncertain:1

Jun 28, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.4	M;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.90	P;.;.;.
Vest4		0.93
MutPred		0.40		Gain of ubiquitination at K2156 (P = 0.0804);.;.;.;
MVP		0.87
MPC		0.49
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.74
gMVP		0.59

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: rs1555111106; hg19: chr11-76924941;