20-33657974-G-A

Position:

• chr20-33657974-G-A

Variant summary

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

The NM_031232.4(NECAB3):​c.1130C>T​(p.Ala377Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,405,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NECAB3 NM_031232.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

Genes affected

NECAB3 (HGNC:15851): (N-terminal EF-hand calcium binding protein 3) The protein encoded by this gene interacts with the amino-terminal domain of the neuron-specific X11-like protein (X11L), inhibits the association of X11L with amyloid precursor protein through a non-competitive mechanism, and abolishes the suppression of beta-amyloid production by X11L. This protein, together with X11L, may play an important role in the regulatory system of amyloid precursor protein metabolism and beta-amyloid generation. The protein is phosphorylated by NIMA-related expressed kinase 2, and localizes to the Golgi apparatus. Multiple transcript variants encoding different isoforms have been found for this gene. [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=0.15234146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECAB3	NM_031232.4	c.1130C>T	p.Ala377Val	missense_variant	11/12	ENST00000246190.11	NP_112509.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECAB3	ENST00000246190.11	c.1130C>T	p.Ala377Val	missense_variant	11/12	5	NM_031232.4	ENSP00000246190.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405144 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 693776

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: 9.24e-7

Gnomad4 OTH exome AF: 0.00

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

Dec 11, 2023

The c.1130C>T (p.A377V) alteration is located in exon 11 (coding exon 11) of the NECAB3 gene. This alteration results from a C to T substitution at nucleotide position 1130, causing the alanine (A) at amino acid position 377 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Benign	0.023
Sift	Benign	0.14	T;T;.
Sift4G	Benign	0.15	T;T;.
Polyphen		0.0040	B;B;.
Vest4		0.29
MutPred		0.23		Loss of catalytic residue at A377 (P = 0.1707);.;.;
MVP		0.14
MPC		0.32
ClinPred		0.44	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.22

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: rs1409390821; hg19: chr20-32245780;