11-6396164-C-T

Position:

• chr11-6396164-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001164.5(APBB1):​c.1724G>A​(p.Arg575His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,399,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: APBB1 NM_001164.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

Genes affected

APBB1 (HGNC:581): (amyloid beta precursor protein binding family B member 1) The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in the nucleus. It interacts with the Alzheimer's disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene product's nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimer's disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Mar 2012]

APBB1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23062694).
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APBB1	NM_001164.5	c.1724G>A	p.Arg575His	missense_variant	13/15	ENST00000609360.6	NP_001155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APBB1	ENST00000609360.6	c.1724G>A	p.Arg575His	missense_variant	13/15	5	NM_001164.5	ENSP00000477213.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000500 AC: 7 AN: 1399658 Hom.: 0 Cov.: 32 AF XY: 0.00000579 AC XY: 4 AN XY: 690592

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: 0.00000463

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2024

The c.1724G>A (p.R575H) alteration is located in exon 13 (coding exon 12) of the APBB1 gene. This alteration results from a G to A substitution at nucleotide position 1724, causing the arginine (R) at amino acid position 575 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.059	T;T;T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.68	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;.;.;D;D;.;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	.;.;.;.;.;.;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.0	.;.;.;N;.;.;N;.;N;.;.;.;.;N
REVEL	Benign	0.14
Sift	Uncertain	0.015	.;.;.;D;.;.;D;.;D;.;.;.;.;D
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;D;T;T;T
Polyphen		1.0	.;.;.;.;.;.;D;D;D;.;.;.;.;.
Vest4		0.14
MutPred		0.48		.;.;.;Loss of phosphorylation at S573 (P = 0.0916);.;.;.;Loss of phosphorylation at S573 (P = 0.0916);.;.;.;.;.;.;
MVP		0.43
MPC		0.94
ClinPred		0.86	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.41

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: rs1046276459; hg19: chr11-6417394; COSMIC: COSV100192345; COSMIC: COSV100192345;