chr9-69431332-T-G

Position:

• chr9-69431332-T-G

Variant summary

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

The NM_001163.4(APBA1):​c.2509A>C​(p.Ile837Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APBA1 NM_001163.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

Genes affected

APBA1 (HGNC:578): (amyloid beta precursor protein binding family A member 1) The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adapter protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilizes APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. [provided by RefSeq, Jul 2008]

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=0.19249439).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APBA1	NM_001163.4	c.2509A>C	p.Ile837Leu	missense_variant	13/13	ENST00000265381.7	NP_001154.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APBA1	ENST00000265381.7	c.2509A>C	p.Ile837Leu	missense_variant	13/13	1	NM_001163.4	ENSP00000265381.3
APBA1	ENST00000699288.1	c.1354A>C	p.Ile452Leu	missense_variant	12/12			ENSP00000514269.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jun 10, 2022

The c.2509A>C (p.I837L) alteration is located in exon 13 (coding exon 12) of the APBA1 gene. This alteration results from a A to C substitution at nucleotide position 2509, causing the isoleucine (I) at amino acid position 837 to be replaced by a leucine (L). 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.46	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.18
Sift	Benign	0.15	T
Sift4G	Benign	0.51	T
Polyphen		0.031	B
Vest4		0.35
MutPred		0.33		Gain of disorder (P = 0.0823);
MVP		0.66
MPC		1.5
ClinPred		0.83	D
GERP RS		4.3
Varity_R		0.15
gMVP		0.36

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: rs1834590015; hg19: chr9-72046248;