22-39045429-A-C

Position:

• chr22-39045429-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_145298.6(APOBEC3F):​c.453A>C​(p.Glu151Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,112 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (19 hom.)
• Consequence: APOBEC3F NM_145298.6 missense, splice_region
• Scores: Splicing: ADA: 0.00003422
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.75

Genes affected

APOBEC3F (HGNC:17356): (apolipoprotein B mRNA editing enzyme catalytic subunit 3F) This gene is a member of the cytidine deaminase gene family. It is one of seven related genes or pseudogenes found in a cluster, thought to result from gene duplication, on chromosome 22. Members of the cluster encode proteins that are structurally and functionally related to the C to U RNA-editing cytidine deaminase APOBEC1. It is thought that the proteins may be RNA editing enzymes and have roles in growth or cell cycle control. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009129643).
• BP6: Variant 22-39045429-A-C is Benign according to our data. Variant chr22-39045429-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 731745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOBEC3F	NM_145298.6	c.453A>C	p.Glu151Asp	missense_variant, splice_region_variant	4/7	ENST00000308521.10	NP_660341.2
APOBEC3F	XM_047441184.1	c.660A>C	p.Glu220Asp	missense_variant	3/6		XP_047297140.1
APOBEC3F	XM_047441185.1	c.453A>C	p.Glu151Asp	missense_variant, splice_region_variant	4/5		XP_047297141.1
APOBEC3F	XM_017028642.3	c.453A>C	p.Glu151Asp	missense_variant, splice_region_variant	4/5		XP_016884131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOBEC3F	ENST00000308521.10	c.453A>C	p.Glu151Asp	missense_variant, splice_region_variant	4/7	1	NM_145298.6	ENSP00000309749	P1
APOBEC3F	ENST00000476513.1	n.246A>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00189 AC: 476 AN: 251450 Hom.: 3 AF XY: 0.00244 AC XY: 331 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00768

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00130 AC: 1895 AN: 1461864 Hom.: 19 Cov.: 34 AF XY: 0.00161 AC XY: 1174 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00860

Gnomad4 FIN exome AF: 0.00369

Gnomad4 NFE exome AF: 0.000764

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74430

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000601

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00202 AC: 245

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.033
DANN	Benign	0.66
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.20	T
Sift4G	Benign	0.41	T
Polyphen		0.0040	B
Vest4		0.13
MutPred		0.84		Gain of phosphorylation at Y154 (P = 0.1623);
MVP		0.18
MPC		0.33
ClinPred		0.024	T
GERP RS		-4.5
Varity_R		0.072
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs147329876; hg19: chr22-39441434;