5-140561643-A-G

Variant names:

• chr5-140561643-A-G
• rs250430
• NM_133173.3:c.691T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133173.3(APBB3):​c.691T>C​(p.Cys231Arg) variant causes a missense change. The variant allele was found at a frequency of 0.864 in 1,614,146 control chromosomes in the GnomAD database, including 602,784 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (59239 hom., cov: 34)
  • Exomes 𝑓: 0.86 (543545 hom.)
• Consequence: APBB3 NM_133173.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74
• Publications: 40 publications found

Genes affected

APBB3 (HGNC:20708): (amyloid beta precursor protein binding family B member 3) The protein encoded by this gene is a member of the APBB protein family. It is found in the cytoplasm and binds to the intracellular domain of the Alzheimer's disease beta-amyloid precursor protein (APP) as well as to other APP-like proteins. It is thought that the protein encoded by this gene may modulate the internalization of APP. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1325994E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133173.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBB3	NM_133173.3	MANE Select	c.691T>C	p.Cys231Arg	missense	Exon 8 of 13	NP_573419.2
	APBB3	NM_006051.4		c.712T>C	p.Cys238Arg	missense	Exon 8 of 13	NP_006042.3
	APBB3	NM_133172.3		c.706T>C	p.Cys236Arg	missense	Exon 7 of 12	NP_573418.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBB3	ENST00000357560.9	TSL:5 MANE Select	c.691T>C	p.Cys231Arg	missense	Exon 8 of 13	ENSP00000350171.4
	APBB3	ENST00000356738.6	TSL:1	c.706T>C	p.Cys236Arg	missense	Exon 7 of 12	ENSP00000349177.2
	APBB3	ENST00000412920.7	TSL:1	c.685T>C	p.Cys229Arg	missense	Exon 7 of 12	ENSP00000402591.3

Frequencies

GnomAD3 genomes AF: 0.881 AC: 133997 AN: 152178 Hom.: 59188 Cov.: 34

Gnomad AFR AF: 0.941

Gnomad AMI AF: 0.908

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.832

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.886

GnomAD2 exomes AF: 0.866 AC: 217621 AN: 251432 AF XY: 0.868

Gnomad AFR exome AF: 0.939

Gnomad AMR exome AF: 0.841

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.888

Gnomad FIN exome AF: 0.796

Gnomad NFE exome AF: 0.861

Gnomad OTH exome AF: 0.863

GnomAD4 exome AF: 0.862 AC: 1259833 AN: 1461850 Hom.: 543545 Cov.: 82 AF XY: 0.864 AC XY: 628090 AN XY: 727228

African (AFR) AF: 0.940 AC: 31464 AN: 33480

American (AMR) AF: 0.844 AC: 37744 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 21764 AN: 26136

East Asian (EAS) AF: 0.888 AC: 35267 AN: 39700

South Asian (SAS) AF: 0.912 AC: 78695 AN: 86258

European-Finnish (FIN) AF: 0.794 AC: 42424 AN: 53412

Middle Eastern (MID) AF: 0.921 AC: 5312 AN: 5768

European-Non Finnish (NFE) AF: 0.858 AC: 954423 AN: 1111978

Other (OTH) AF: 0.873 AC: 52740 AN: 60394

GnomAD4 genome AF: 0.881 AC: 134106 AN: 152296 Hom.: 59239 Cov.: 34 AF XY: 0.877 AC XY: 65296 AN XY: 74456

African (AFR) AF: 0.941 AC: 39114 AN: 41572

American (AMR) AF: 0.867 AC: 13256 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 2889 AN: 3472

East Asian (EAS) AF: 0.893 AC: 4619 AN: 5170

South Asian (SAS) AF: 0.904 AC: 4366 AN: 4832

European-Finnish (FIN) AF: 0.798 AC: 8459 AN: 10606

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58413 AN: 68024

Other (OTH) AF: 0.888 AC: 1878 AN: 2116

Alfa AF: 0.870 Hom.: 200537

Bravo AF: 0.889

TwinsUK AF: 0.865 AC: 3207

ALSPAC AF: 0.861 AC: 3319

ESP6500AA AF: 0.939 AC: 4137

ESP6500EA AF: 0.865 AC: 7436

ExAC AF: 0.869 AC: 105541

Asia WGS AF: 0.909 AC: 3164 AN: 3478

EpiCase AF: 0.872

EpiControl AF: 0.873

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.4	N
PhyloP100		6.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	7.2	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MPC		0.44
ClinPred		0.013	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.62
Mutation Taster		=99/1	polymorphism (auto)

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: rs250430; hg19: chr5-139941228; COSMIC: COSV60051909; COSMIC: COSV60051909;