19-48905780-T-A

Position:

• chr19-48905780-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006184.6(NUCB1):​c.271T>A​(p.Phe91Ile) 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: 31)
• Consequence: NUCB1 NM_006184.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30985057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUCB1	NM_006184.6	c.271T>A	p.Phe91Ile	missense_variant	4/13	ENST00000405315.9	NP_006175.2
NUCB1	XM_017026845.2	c.271T>A	p.Phe91Ile	missense_variant	4/13		XP_016882334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUCB1	ENST00000405315.9	c.271T>A	p.Phe91Ile	missense_variant	4/13	1	NM_006184.6	ENSP00000385923	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000227

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

Apr 25, 2022

The c.271T>A (p.F91I) alteration is located in exon 4 (coding exon 3) of the NUCB1 gene. This alteration results from a T to A substitution at nucleotide position 271, causing the phenylalanine (F) at amino acid position 91 to be replaced by an isoleucine (I). 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	0.88
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D;.;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N;N;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.047	D;D;D;D;D
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.87	P;P;.;.;.
Vest4		0.52
MutPred		0.23		Gain of MoRF binding (P = 0.0865);Gain of MoRF binding (P = 0.0865);Gain of MoRF binding (P = 0.0865);Gain of MoRF binding (P = 0.0865);Gain of MoRF binding (P = 0.0865);
MVP		0.47
MPC		0.62
ClinPred		0.96	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.29

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: rs897045509; hg19: chr19-49409037;