11-77204088-A-T

Variant names:

• chr11-77204088-A-T
• NM_000260.4:c.5339A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000260.4(MYO7A):​c.5339A>T​(p.Tyr1780Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,732 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.

• 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: 5.78

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.

• PM1: In a domain MyTH4 2 (size 149) in uniprot entity MYO7A_HUMAN there are 15 pathogenic changes around while only 5 benign (75%) in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5339A>T	p.Tyr1780Phe	missense_variant	Exon 39 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5339A>T	p.Tyr1780Phe	missense_variant	Exon 39 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5225A>T	p.Tyr1742Phe	missense_variant	Exon 39 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5192A>T	p.Tyr1731Phe	missense_variant	Exon 40 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2765A>T	p.Tyr922Phe	missense_variant	Exon 19 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.3167-2A>T		splice_acceptor_variant, intron_variant	Intron 21 of 31			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448732 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719298

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.037	D;D;D;D
Sift4G	Benign	0.094	T;T;T;D
Polyphen		0.80	P;.;.;.
Vest4		0.55
MutPred		0.64		Gain of ubiquitination at K1779 (P = 0.0626);.;.;.;
MVP		0.90
MPC		0.12
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.62
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-76915133;