3-43366459-C-T

Position:

• chr3-43366459-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018075.5(ANO10):​c.*447G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 295,332 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (6 hom.)
• Consequence: ANO10 NM_018075.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.09

Genes affected

ANO10 (HGNC:25519): (anoctamin 10) The transmembrane protein encoded by this gene belongs to the anoctamin family of calcium-activated chloride channels, also known as the transmembrane 16 family. The encoded protein contains eight transmembrane domains with cytosolic N- and C-termini. Defects in this gene may cause autosomal recessive spinocerebellar ataxia-10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

SNRK (HGNC:30598): (SNF related kinase) SNRK is a member of the sucrose nonfermenting (SNF)-related kinase family of serine/threonine kinases (Kertesz et al., 2002 [PubMed 12234663]).[supplied by OMIM, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-43366459-C-T is Benign according to our data. Variant chr3-43366459-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345163.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00695 (1059/152298) while in subpopulation NFE AF= 0.0116 (792/68016). AF 95% confidence interval is 0.011. There are 8 homozygotes in gnomad4. There are 512 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO10	NM_018075.5	c.*447G>A		3_prime_UTR_variant	13/13	ENST00000292246.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO10	ENST00000292246.8	c.*447G>A		3_prime_UTR_variant	13/13	1	NM_018075.5	P1
ANO10	ENST00000350459.8	c.*447G>A		3_prime_UTR_variant	12/12	1
ANO10	ENST00000396091.7	c.*447G>A		3_prime_UTR_variant	12/12	2
SNRK	ENST00000468628.2	n.230+4591C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1059 AN: 152180 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.00819 AC: 1171 AN: 143034 Hom.: 6 Cov.: 0 AF XY: 0.00756 AC XY: 574 AN XY: 75930

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.00424

Gnomad4 ASJ exome AF: 0.00758

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.00976

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00947

GnomAD4 genome AF: 0.00695 AC: 1059 AN: 152298 Hom.: 8 Cov.: 32 AF XY: 0.00688 AC XY: 512 AN XY: 74470

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00855 Hom.: 0

Bravo AF: 0.00642

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

ANO10: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs112787589; hg19: chr3-43407951;