19-48913011-G-A

Position:

• chr19-48913011-G-A

Variant summary

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

The NM_006184.6(NUCB1):​c.481G>A​(p.Ala161Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NUCB1 NM_006184.6 missense, splice_region
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.81

Genes affected

NUCB1 (HGNC:8043): (nucleobindin 1) This gene encodes a member of a small calcium-binding EF-hand protein family. The encoded protein is thought to have a key role in Golgi calcium homeostasis and Ca(2+)-regulated signal transduction events. [provided by RefSeq, Jun 2010]

NUCB1 (HGNC:):

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
NUCB1	NM_006184.6	c.481G>A	p.Ala161Thr	missense_variant, splice_region_variant	6/13	ENST00000405315.9	NP_006175.2
NUCB1	XM_017026845.2	c.481G>A	p.Ala161Thr	missense_variant, splice_region_variant	6/13		XP_016882334.1
NUCB1-AS1	NR_046633.1	n.189-1837C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUCB1	ENST00000405315.9	c.481G>A	p.Ala161Thr	missense_variant, splice_region_variant	6/13	1	NM_006184.6	ENSP00000385923.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450662 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 720970

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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 27, 2024

The c.481G>A (p.A161T) alteration is located in exon 6 (coding exon 5) of the NUCB1 gene. This alteration results from a G to A substitution at nucleotide position 481, causing the alanine (A) at amino acid position 161 to be replaced by a threonine (T). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.48	T;T;T
Sift4G	Benign	0.25	T;T;D
Polyphen		0.95	P;P;.
Vest4		0.74
MutPred		0.50		Gain of catalytic residue at A161 (P = 0.0241);Gain of catalytic residue at A161 (P = 0.0241);Gain of catalytic residue at A161 (P = 0.0241);
MVP		0.59
MPC		0.56
ClinPred		0.92	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49416268;