Variant chr1-19657022-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005380.8(NBL1):c.439G>A(p.Gly147Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000955 in 1,570,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000085 ( 0 hom. )

Consequence

NBL1
NM_005380.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.635

Variant links:

Genes affected

NBL1 (HGNC:7650): (NBL1, DAN family BMP antagonist) This gene product is the founding member of the evolutionarily conserved CAN (Cerberus and DAN) family of proteins, which contain a domain resembling the CTCK (C-terminal cystine knot-like) motif found in a number of signaling molecules. These proteins are secreted, and act as BMP (bone morphogenetic protein) antagonists by binding to BMPs and preventing them from interacting with their receptors. They may thus play an important role during growth and development. Alternatively spliced transcript variants have been identified for this gene. Read-through transcripts between this locus and the upstream mitochondrial inner membrane organizing system 1 gene (GeneID 440574) have been observed. [provided by RefSeq, May 2013]

NBL1 links:

MICOS10-NBL1 (HGNC:):

MICOS10-NBL1 links:

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ACMG classification

Classification made for transcript

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=0.085125655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBL1	NM_005380.8 linkuse as main transcript	c.439G>A	p.Gly147Ser	missense_variant	4/4	ENST00000375136.8
MICOS10-NBL1	NM_001204088.2 linkuse as main transcript	c.481G>A	p.Gly161Ser	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBL1	ENST00000375136.8 linkuse as main transcript	c.439G>A	p.Gly147Ser	missense_variant	4/4	1	NM_005380.8	P1	P41271-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000344

AC:

AN:

174496

Hom.:

AF XY:

0.0000213

AC XY:

AN XY:

93824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000409

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000846

AC:

AN:

1418546

Hom.:

Cov.:

AF XY:

0.00000712

AC XY:

AN XY:

701892

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000790

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000246

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000550

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151760

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74120

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000171

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.481G>A (p.G161S) alteration is located in exon 5 (coding exon 4) of the MINOS1-NBL1 gene. This alteration results from a G to A substitution at nucleotide position 481, causing the glycine (G) at amino acid position 161 to be replaced by a serine (S). 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

0.075

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;T;T;T;T;.;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.77

.;T;.;.;.;.;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.085

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;N;N;N;N;.;.;N

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.37

.;N;.;.;N;.;.;N;.

REVEL

Benign

0.022

Sift

Benign

0.22

.;T;.;.;T;.;.;T;.

Sift4G

Benign

0.24

T;T;T;T;T;T;T;T;T

Polyphen

0.98

.;D;.;.;.;.;.;.;.

Vest4

0.10

MVP

0.37

MPC

1.3

ClinPred

0.097

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over