11-77156683-C-A

Variant names:

• chr11-77156683-C-A
• NM_000260.4:c.494C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000260.4(MYO7A):​c.494C>A​(p.Thr165Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T165M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a binding_site (size 7) in uniprot entity MYO7A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77156683-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.494C>A	p.Thr165Lys	missense_variant	Exon 6 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.494C>A	p.Thr165Lys	missense_variant	Exon 6 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.494C>A	p.Thr165Lys	missense_variant	Exon 6 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.461C>A	p.Thr154Lys	missense_variant	Exon 7 of 50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727122

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.;H;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.0	D;.;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.97
MutPred		0.86		Gain of ubiquitination at T165 (P = 0.0203);Gain of ubiquitination at T165 (P = 0.0203);Gain of ubiquitination at T165 (P = 0.0203);.;
MVP		0.98
MPC		0.51
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-76867729;