12-100942432-G-T

Variant names:

• chr12-100942432-G-T
• NM_001286615.2:c.353G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001286615.2(ANO4):​c.353G>T​(p.Arg118Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO4 NM_001286615.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.99
• Publications: 0 publications found

Genes affected

ANO4 (HGNC:23837): (anoctamin 4) Enables intracellular calcium activated chloride channel activity. Involved in chloride transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ANO4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5332 (below the threshold of 3.09). Trascript score misZ: 3.1552 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO4	NM_001286615.2	c.353G>T	p.Arg118Leu	missense_variant	Exon 5 of 28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8	c.353G>T	p.Arg118Leu	missense_variant	Exon 5 of 28	2	NM_001286615.2	ENSP00000376703.3
ANO4	ENST00000644049.1	c.851G>T	p.Arg284Leu	missense_variant	Exon 7 of 30			ENSP00000494481.1
ANO4	ENST00000392979.7	c.248G>T	p.Arg83Leu	missense_variant	Exon 4 of 27	2		ENSP00000376705.3
ANO4	ENST00000549155.6	n.851G>T		non_coding_transcript_exon_variant	Exon 7 of 11	2		ENSP00000449116.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.248G>T (p.R83L) alteration is located in exon 4 (coding exon 3) of the ANO4 gene. This alteration results from a G to T substitution at nucleotide position 248, causing the arginine (R) at amino acid position 83 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.2	.;.;M
PhyloP100		7.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.2	.;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0040	.;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.65, 0.68
MutPred		0.52		.;.;Loss of MoRF binding (P = 0.0152);
MVP		0.23
MPC		0.77
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.65
gMVP		0.59
Mutation Taster		=28/72	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

hg19: chr12-101336210; COSMIC: COSV54607261;