14-23061501-C-G

Variant names:

• chr14-23061501-C-G
• rs974185778
• NM_001386863.1:c.3221G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001386863.1(ACIN1):​c.3221G>C​(p.Arg1074Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1074Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 13)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACIN1 NM_001386863.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34013924).

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.3221G>C	p.Arg1074Pro	missense	Exon 17 of 19	NP_001373792.1	S4R3H4
	ACIN1	NM_014977.4		c.3395G>C	p.Arg1132Pro	missense	Exon 17 of 19	NP_055792.2	Q9UKV3-1
	ACIN1	NM_001164814.2		c.3356G>C	p.Arg1119Pro	missense	Exon 17 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.3221G>C	p.Arg1074Pro	missense	Exon 17 of 19	ENSP00000474349.1	S4R3H4
	ACIN1	ENST00000262710.5	TSL:1	c.3395G>C	p.Arg1132Pro	missense	Exon 17 of 19	ENSP00000262710.1	Q9UKV3-1
	ACIN1	ENST00000555053.5	TSL:1	c.3356G>C	p.Arg1119Pro	missense	Exon 17 of 19	ENSP00000451328.1	Q9UKV3-5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 56938 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000888 AC: 2 AN: 225230 AF XY: 0.0000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000145 AC: 1 AN: 691524 Hom.: 0 Cov.: 49 AF XY: 0.00 AC XY: 0 AN XY: 342798

⚠️ 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: 16550

American (AMR) AF: 0.00 AC: 0 AN: 29842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11632

East Asian (EAS) AF: 0.00 AC: 0 AN: 10864

South Asian (SAS) AF: 0.00 AC: 0 AN: 47190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3278

European-Non Finnish (NFE) AF: 0.00000191 AC: 1 AN: 522694

Other (OTH) AF: 0.00 AC: 0 AN: 24790

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 56938 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 27352

African (AFR) AF: 0.00 AC: 0 AN: 13566

American (AMR) AF: 0.00 AC: 0 AN: 3950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1618

East Asian (EAS) AF: 0.00 AC: 0 AN: 2108

South Asian (SAS) AF: 0.00 AC: 0 AN: 1596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 30826

Other (OTH) AF: 0.00 AC: 0 AN: 702

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Benign	0.047	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.35		Gain of glycosylation at R1132 (P = 0.0104)
MVP		0.45
MPC		2.5
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.37
gMVP		0.48
Mutation Taster		=38/62	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

dbSNP: rs974185778; hg19: chr14-23530710;