NM_005380.8:c.317C>A

Variant names:

• chr1-19656900-C-A
• rs1325628774
• NM_005380.8:c.317C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005380.8(NBL1):​c.317C>A​(p.Pro106His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NBL1 NM_005380.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32
• Publications: 1 publications found

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:48338): (MICOS10-NBL1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring chromosome 1 open reading frame 151 (GeneID 440574) and neuroblastoma suppressor of tumorigenicity 1 (GeneID 4681) genes on chromosome 1. The read-through transcripts produce at least two proteins, each of which share identity with proteins translated from the downstream neuroblastoma suppressor of tumorigenicity 1 locus. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005380.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBL1	NM_005380.8	MANE Select	c.317C>A	p.Pro106His	missense	Exon 4 of 4	NP_005371.2	P41271-1
	NBL1	NM_182744.4		c.422C>A	p.Pro141His	missense	Exon 4 of 4	NP_877421.2	P41271-2
	NBL1	NM_001204086.3		c.419C>A	p.Pro140His	missense	Exon 4 of 4	NP_001191015.1	A0A087WTY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBL1	ENST00000375136.8	TSL:1 MANE Select	c.317C>A	p.Pro106His	missense	Exon 4 of 4	ENSP00000364278.4	P41271-1
	NBL1	ENST00000615215.4	TSL:1	c.419C>A	p.Pro140His	missense	Exon 4 of 4	ENSP00000478223.1	A0A087WTY6
	NBL1	ENST00000618761.4	TSL:1	c.317C>A	p.Pro106His	missense	Exon 4 of 4	ENSP00000483061.1	P41271-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000813 AC: 2 AN: 246130 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460938 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726724

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000448 AC: 2 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111506

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.62
MPC		1.4
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.86
gMVP		0.82
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs1325628774; hg19: chr1-19983393; COSMIC: COSV57030020; COSMIC: COSV57030020;