12-7649551-C-T

Variant names:

• chr12-7649551-C-T
• rs12820011
• NM_001644.5:c.707G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001644.5(APOBEC1):​c.707G>A​(p.Arg236Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,034 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: APOBEC1 NM_001644.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.401

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038268447).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOBEC1	NM_001644.5	c.707G>A	p.Arg236Lys	missense_variant	Exon 5 of 5	ENST00000229304.5	NP_001635.2
APOBEC1	NM_001304566.1	c.707G>A	p.Arg236Lys	missense_variant	Exon 6 of 6		NP_001291495.1
APOBEC1	NM_005889.4	c.572G>A	p.Arg191Lys	missense_variant	Exon 4 of 4		NP_005880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOBEC1	ENST00000229304.5	c.707G>A	p.Arg236Lys	missense_variant	Exon 5 of 5	1	NM_001644.5	ENSP00000229304.4
APOBEC1	ENST00000467171.2	n.*568G>A		non_coding_transcript_exon_variant	Exon 4 of 4	1		ENSP00000436415.2
APOBEC1	ENST00000467171.2	n.*568G>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000436415.2

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000716 AC: 180 AN: 251292 Hom.: 1 AF XY: 0.000832 AC XY: 113 AN XY: 135808

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00110 AC: 1604 AN: 1461738 Hom.: 4 Cov.: 30 AF XY: 0.00110 AC XY: 799 AN XY: 727140

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00137

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74472

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00102 Hom.: 2

Bravo AF: 0.000782

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000692 AC: 84

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.707G>A (p.R236K) alteration is located in exon 5 (coding exon 5) of the APOBEC1 gene. This alteration results from a G to A substitution at nucleotide position 707, causing the arginine (R) at amino acid position 236 to be replaced by a lysine (K). 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	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.015
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.15
Sift	Benign	0.043	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.080
MVP		0.58
MPC		0.33
ClinPred		0.037	T
GERP RS		1.9
Varity_R		0.27
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs12820011; hg19: chr12-7802147;