chr3-43366727-G-A

Position:

• chr3-43366727-G-A

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.*179C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 676,920 control chromosomes in the GnomAD database, including 229 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 0.018 (39 hom., cov: 32)
  • Exomes 𝑓: 0.023 (190 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: -1.67

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=-0.86).
• BP6: Variant 3-43366727-G-A is Benign according to our data. Variant chr3-43366727-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345171.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2748/152288) while in subpopulation NFE AF= 0.0311 (2117/68010). AF 95% confidence interval is 0.03. There are 39 homozygotes in gnomad4. There are 1302 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO10	NM_018075.5	c.*179C>T		3_prime_UTR_variant	13/13	ENST00000292246.8	NP_060545.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO10	ENST00000292246.8	c.*179C>T		3_prime_UTR_variant	13/13	1	NM_018075.5	ENSP00000292246	P1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2749 AN: 152170 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00552

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.00910

GnomAD4 exome AF: 0.0229 AC: 12009 AN: 524632 Hom.: 190 Cov.: 6 AF XY: 0.0223 AC XY: 6237 AN XY: 279618

Gnomad4 AFR exome AF: 0.00563

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00414

Gnomad4 EAS exome AF: 0.0000634

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0180 AC: 2748 AN: 152288 Hom.: 39 Cov.: 32 AF XY: 0.0175 AC XY: 1302 AN XY: 74462

Gnomad4 AFR AF: 0.00551

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.0311

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0292 Hom.: 12

Bravo AF: 0.0166

Asia WGS AF: 0.00635 AC: 22 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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.64
DANN	Benign	0.81

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: rs111871863; hg19: chr3-43408219;