11-420756-A-T

Position:

• chr11-420756-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001012302.3(ANO9):​c.1595T>A​(p.Val532Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,454,392 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANO9 NM_001012302.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81

Genes affected

ANO9 (HGNC:20679): (anoctamin 9) The protein encoded by this gene is a member of the TMEM16 (anoctamin) family of proteins, some of which form integral membrane calcium-activated chloride channels. The function of the encoded protein has yet to be elucidated, although it may have channel-forming abilities and also may have phospholipid scramblase activity. This gene has been observed to be upregulated in stage II and III colorectal cancers. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO9	NM_001012302.3	c.1595T>A	p.Val532Asp	missense_variant	18/23	ENST00000332826.7
ANO9	NM_001347882.2	c.1163T>A	p.Val388Asp	missense_variant	17/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO9	ENST00000332826.7	c.1595T>A	p.Val532Asp	missense_variant	18/23	1	NM_001012302.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454392 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 723500

Gnomad4 AFR exome AF: 0.0000599

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.030
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.054	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.68		Gain of relative solvent accessibility (P = 0.0166);
MVP		0.47
MPC		1.1
ClinPred		0.97	D
GERP RS		3.7
Varity_R		0.26
gMVP		0.86

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: rs1475040565; hg19: chr11-420756;