20-33659673-T-C

Position:

• chr20-33659673-T-C

Variant summary

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

The NM_031232.4(NECAB3):​c.703A>G​(p.Ile235Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NECAB3 NM_031232.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NECAB3	NM_031232.4	c.703A>G	p.Ile235Val	missense_variant	8/12	ENST00000246190.11	NP_112509.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NECAB3	ENST00000246190.11	c.703A>G	p.Ile235Val	missense_variant	8/12	5	NM_031232.4	ENSP00000246190.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1458118 Hom.: 0 Cov.: 33 AF XY: 0.00000827 AC XY: 6 AN XY: 725402

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000404

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-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

Feb 21, 2024

The c.703A>G (p.I235V) alteration is located in exon 8 (coding exon 8) of the NECAB3 gene. This alteration results from a A to G substitution at nucleotide position 703, causing the isoleucine (I) at amino acid position 235 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	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;.;.;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;T;T;D;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	2.9	M;M;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.91	N;N;.;.;N
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;D;.;.;D
Sift4G	Uncertain	0.0090	D;D;.;.;.
Polyphen		0.99	D;D;.;.;.
Vest4		0.44
MutPred		0.49		Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);.;Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);
MVP		0.31
MPC		0.82
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
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: rs2017398405; hg19: chr20-32247479;