rs2047337124

Variant names:

• chr14-23063047-C-T
• rs2047337124
• NM_001386863.1:c.2765G>A

Variant summary

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

The NM_001386863.1(ACIN1):​c.2765G>A​(p.Arg922His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACIN1 NM_001386863.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.45
• Publications: 0 publications found

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]

ENSG00000288795 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30497736).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386863.1. 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
	ACIN1	NM_001386863.1	MANE Select	c.2765G>A	p.Arg922His	missense	Exon 14 of 19	NP_001373792.1	S4R3H4
	ACIN1	NM_014977.4		c.2939G>A	p.Arg980His	missense	Exon 14 of 19	NP_055792.2	Q9UKV3-1
	ACIN1	NM_001164814.2		c.2900G>A	p.Arg967His	missense	Exon 14 of 19	NP_001158286.2	Q9UKV3-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACIN1	ENST00000605057.6	TSL:1 MANE Select	c.2765G>A	p.Arg922His	missense	Exon 14 of 19	ENSP00000474349.1	S4R3H4
	ACIN1	ENST00000262710.5	TSL:1	c.2939G>A	p.Arg980His	missense	Exon 14 of 19	ENSP00000262710.1	Q9UKV3-1
	ACIN1	ENST00000555053.5	TSL:1	c.2900G>A	p.Arg967His	missense	Exon 14 of 19	ENSP00000451328.1	Q9UKV3-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460846 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726756

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111672

Other (OTH) AF: 0.00 AC: 0 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000192981), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.18		Loss of MoRF binding (P = 0.0261)
MVP		0.67
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.81
Mutation Taster		=51/49	polymorphism

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: rs2047337124; hg19: chr14-23532256;