12-7652828-T-C

Variant names:

• chr12-7652828-T-C
• rs1565440016
• NM_001644.5:c.52A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001644.5(APOBEC1):​c.52A>G​(p.Ile18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,990 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: APOBEC1 NM_001644.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

APOBEC1 (HGNC:604): (apolipoprotein B mRNA editing enzyme catalytic subunit 1) This gene encodes a member of the cytidine deaminase enzyme family. The encoded protein forms a multiple-protein editing holoenzyme with APOBEC1 complementation factor (ACF) and APOBEC1 stimulating protein (ASP). This holoenzyme is involved in the editing of C-to-U nucleotide bases in apolipoprotein B and neurofibromatosis-1 mRNAs. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOBEC1	NM_001644.5	c.52A>G	p.Ile18Val	missense_variant	Exon 3 of 5	ENST00000229304.5	NP_001635.2
APOBEC1	NM_001304566.1	c.52A>G	p.Ile18Val	missense_variant	Exon 4 of 6		NP_001291495.1
APOBEC1	NM_005889.4	c.-84A>G		5_prime_UTR_variant	Exon 2 of 4		NP_005880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOBEC1	ENST00000229304.5	c.52A>G	p.Ile18Val	missense_variant	Exon 3 of 5	1	NM_001644.5	ENSP00000229304.4
APOBEC1	ENST00000467171.2	n.24A>G		non_coding_transcript_exon_variant	Exon 2 of 4	1		ENSP00000436415.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425990 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 705944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

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 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52A>G (p.I18V) alteration is located in exon 3 (coding exon 3) of the APOBEC1 gene. This alteration results from a A to G substitution at nucleotide position 52, causing the isoleucine (I) at amino acid position 18 to be replaced by a valine (V). 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	0.22
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.26
Sift	Benign	0.080	T
Sift4G	Uncertain	0.047	D
Polyphen		0.97	D
Vest4		0.30
MutPred		0.72		Loss of catalytic residue at P20 (P = 0.0306);
MVP		0.71
MPC		0.95
ClinPred		0.92	D
GERP RS		3.3
Varity_R		0.11
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1565440016; hg19: chr12-7805424;