22-38985864-G-A

Variant names:

• chr22-38985864-G-A
• rs770721127
• NM_004900.5:c.227G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004900.5(APOBEC3B):​c.227G>A​(p.Cys76Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: APOBEC3B NM_004900.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0720

Genes affected

APOBEC3B (HGNC:17352): (apolipoprotein B mRNA editing enzyme catalytic subunit 3B) 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. A hybrid gene results from the deletion of approximately 29.5 kb of sequence between this gene, APOBEC3B, and the adjacent gene APOBEC3A. The breakpoints of the deletion are within the two genes, so the deletion allele is predicted to have the promoter and coding region of APOBEC3A, but the 3' UTR of APOBEC3B. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07761228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOBEC3B	NM_004900.5	c.227G>A	p.Cys76Tyr	missense_variant	Exon 3 of 8	ENST00000333467.4	NP_004891.5
APOBEC3B	NM_001270411.2	c.227G>A	p.Cys76Tyr	missense_variant	Exon 3 of 8		NP_001257340.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOBEC3B	ENST00000333467.4	c.227G>A	p.Cys76Tyr	missense_variant	Exon 3 of 8	1	NM_004900.5	ENSP00000327459.3
APOBEC3B	ENST00000407298.7	c.227G>A	p.Cys76Tyr	missense_variant	Exon 3 of 8	1		ENSP00000385068.3
APOBEC3B	ENST00000335760.9	n.227G>A		non_coding_transcript_exon_variant	Exon 3 of 7	1		ENSP00000338897.5
APOBEC3B	ENST00000402182.7	c.227G>A	p.Cys76Tyr	missense_variant	Exon 3 of 7	2		ENSP00000385060.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 81

GnomAD4 genome Cov.: 29

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.227G>A (p.C76Y) alteration is located in exon 3 (coding exon 3) of the APOBEC3B gene. This alteration results from a G to A substitution at nucleotide position 227, causing the cysteine (C) at amino acid position 76 to be replaced by a tyrosine (Y). 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	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.24
DANN	Benign	0.38
DEOGEN2	Benign	0.082	.;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.090
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.097	T;T;T
Polyphen		0.72	.;.;P
Vest4		0.11
MutPred		0.32		Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);
MVP		0.53
MPC		3.4
ClinPred		0.18	T
GERP RS		-0.56
Varity_R		0.21
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770721127; hg19: chr22-39381869;