12-100939407-A-C

Variant names:

• chr12-100939407-A-C
• NM_001286615.2:c.253A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001286615.2(ANO4):​c.253A>C​(p.Thr85Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar 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: 7.17
• 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41857845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO4	NM_001286615.2	c.253A>C	p.Thr85Pro	missense_variant	Exon 4 of 28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8	c.253A>C	p.Thr85Pro	missense_variant	Exon 4 of 28	2	NM_001286615.2	ENSP00000376703.3
ANO4	ENST00000644049.1	c.751A>C	p.Thr251Pro	missense_variant	Exon 6 of 30			ENSP00000494481.1
ANO4	ENST00000392979.7	c.148A>C	p.Thr50Pro	missense_variant	Exon 3 of 27	2		ENSP00000376705.3
ANO4	ENST00000549155.6	n.751A>C		non_coding_transcript_exon_variant	Exon 6 of 11	2		ENSP00000449116.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148A>C (p.T50P) alteration is located in exon 3 (coding exon 2) of the ANO4 gene. This alteration results from a A to C substitution at nucleotide position 148, causing the threonine (T) at amino acid position 50 to be replaced by a proline (P). 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	Benign	0.10
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	.;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	.;.;L
PhyloP100		7.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.55	.;N;N
REVEL	Benign	0.26
Sift	Benign	0.27	.;T;T
Sift4G	Benign	0.28	.;T;T
Polyphen		1.0, 0.28	.;D;B
Vest4		0.45, 0.32
MutPred		0.20		.;.;Loss of sheet (P = 0.0037);
MVP		0.068
MPC		1.1
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.28
gMVP		0.25
Mutation Taster		=45/55	disease causing

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

Other links and lift over

hg19: chr12-101333185;