14-23066007-C-T

Position:

• chr14-23066007-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001386863.1(ACIN1):​c.2267G>A​(p.Ser756Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACIN1 NM_001386863.1 missense, splice_region
• Scores: Splicing: ADA: 0.9880
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

Genes affected

ACIN1 (HGNC:17066): (apoptotic chromatin condensation inducer 1) Apoptosis is defined by several morphologic nuclear changes, including chromatin condensation and nuclear fragmentation. This gene encodes a nuclear protein that induces apoptotic chromatin condensation after activation by caspase-3, without inducing DNA fragmentation. This protein has also been shown to be a component of a splicing-dependent multiprotein exon junction complex (EJC) that is deposited at splice junctions on mRNAs, as a consequence of pre-mRNA splicing. It may thus be involved in mRNA metabolism associated with splicing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACIN1	NM_001386863.1	c.2267G>A	p.Ser756Asn	missense_variant, splice_region_variant	10/19	ENST00000605057.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACIN1	ENST00000605057.6	c.2267G>A	p.Ser756Asn	missense_variant, splice_region_variant	10/19	1	NM_001386863.1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.2441G>A (p.S814N) alteration is located in exon 10 (coding exon 10) of the ACIN1 gene. This alteration results from a G to A substitution at nucleotide position 2441, causing the serine (S) at amino acid position 814 to be replaced by an asparagine (N). 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	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.;.;T;.;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.86	D;D;.;D;T;D;D;T;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.24	N;N;N;.;N;N;N;N;N
REVEL	Benign	0.077
Sift	Uncertain	0.0090	D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.036	D;T;T;T;T;T;T;T;.
Polyphen		0.94, 0.87, 0.99	.;P;P;.;D;D;P;.;.
Vest4		0.21
MutPred		0.19		.;.;.;.;Loss of phosphorylation at S814 (P = 0.0034);.;.;Loss of phosphorylation at S814 (P = 0.0034);.;
MVP		0.45
MPC		0.89
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23535216;