3-43580433-A-G

Variant names:

• chr3-43580433-A-G
• rs373386030
• NM_018075.5:c.512T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PP3_Moderate PP5

The NM_018075.5(ANO10):​c.512T>C​(p.Phe171Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004037720: At least one publication reports experimental evidence evaluating an impact on protein function and this variant affects the ANO10 protein function (Petkovic_2020). PMID:34234304" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F171F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ANO10 NM_018075.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.18
• Publications: 5 publications found

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]

ANO10 Gene-Disease associations (from GenCC):

• autosomal recessive spinocerebellar ataxia 10

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004037720: At least one publication reports experimental evidence evaluating an impact on protein function and this variant affects the ANO10 protein function (Petkovic_2020). PMID: 34234304; SCV000612348: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 32620747); SCV004292685: Experimental studies have shown that this missense change affects ANO10 function (PMID: 32620747).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 3-43580433-A-G is Pathogenic according to our data. Variant chr3-43580433-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446836.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018075.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO10	NM_018075.5	MANE Select	c.512T>C	p.Phe171Ser	missense	Exon 5 of 13	NP_060545.3
	ANO10	NM_001346464.2		c.512T>C	p.Phe171Ser	missense	Exon 5 of 14	NP_001333393.1
	ANO10	NM_001346467.2		c.512T>C	p.Phe171Ser	missense	Exon 5 of 14	NP_001333396.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO10	ENST00000292246.8	TSL:1 MANE Select	c.512T>C	p.Phe171Ser	missense	Exon 5 of 13	ENSP00000292246.3	Q9NW15-1
	ANO10	ENST00000350459.8	TSL:1	c.512T>C	p.Phe171Ser	missense	Exon 5 of 12	ENSP00000327767.4	Q9NW15-2
	ANO10	ENST00000970566.1		c.512T>C	p.Phe171Ser	missense	Exon 5 of 15	ENSP00000640625.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251062 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Autosomal recessive spinocerebellar ataxia 10 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.99
MVP		0.81
MPC		0.61
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.95
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs373386030; hg19: chr3-43621925;