1-19657061-G-A

Position:

• chr1-19657061-G-A

Variant summary

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

The NM_005380.8(NBL1):​c.478G>A​(p.Gly160Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,533,732 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 0.000062 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NBL1 NM_005380.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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]

MICOS10-NBL1 (HGNC:):

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=0.07663968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBL1	NM_005380.8	c.478G>A	p.Gly160Arg	missense_variant	4/4	ENST00000375136.8
MICOS10-NBL1	NM_001204088.2	c.520G>A	p.Gly174Arg	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBL1	ENST00000375136.8	c.478G>A	p.Gly160Arg	missense_variant	4/4	1	NM_005380.8	P1

Frequencies

GnomAD3 genomes AF: 0.0000620 AC: 9 AN: 145104 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000454

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000136 AC: 2 AN: 147432 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 79456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000180 AC: 25 AN: 1388628 Hom.: 0 Cov.: 33 AF XY: 0.0000190 AC XY: 13 AN XY: 683742

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.0000847

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.0000254

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000140

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome AF: 0.0000620 AC: 9 AN: 145104 Hom.: 0 Cov.: 27 AF XY: 0.0000567 AC XY: 4 AN XY: 70546

Gnomad4 AFR AF: 0.000102

Gnomad4 AMR AF: 0.000137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000454

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000190 AC: 2

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 05, 2023

The c.520G>A (p.G174R) 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 520, causing the glycine (G) at amino acid position 174 to be replaced by an arginine (R). 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	0.090
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;T;T;T;.;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	.;T;.;.;.;.;T;D;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.077	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;N;N;N;N;.;.;N
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.83	.;N;.;.;N;.;.;N;.
REVEL	Benign	0.024
Sift	Benign	0.80	.;T;.;.;T;.;.;D;.
Sift4G	Benign	0.50	T;T;T;T;T;T;T;D;T
Polyphen		0.0070	.;B;.;.;.;.;.;.;.
Vest4		0.048
MutPred		0.19		.;.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0037);.;
MVP		0.32
MPC		1.5
ClinPred		0.27	T
GERP RS		1.8
Varity_R		0.025
gMVP		0.38

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: rs760069960; hg19: chr1-19983554;