17-80475555-G-T

Variant names:

• chr17-80475555-G-T
• rs1384003832
• NM_002522.4:c.608C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002522.4(NPTX1):​c.608C>A​(p.Thr203Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T203S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NPTX1 NM_002522.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

Genes affected

NPTX1 (HGNC:7952): (neuronal pentraxin 1) NPTX1 is a member of the neuronal pentraxin gene family. Neuronal pentraxin 1 is similar to the rat NP1 gene which encodes a binding protein for the snake venom toxin taipoxin. Human NPTX1 mRNA is exclusively localized to the nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09551531).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPTX1	NM_002522.4	c.608C>A	p.Thr203Asn	missense_variant	Exon 2 of 5	ENST00000306773.5	NP_002513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPTX1	ENST00000306773.5	c.608C>A	p.Thr203Asn	missense_variant	Exon 2 of 5	1	NM_002522.4	ENSP00000307549.4
NPTX1	ENST00000571100.2	c.-107C>A		5_prime_UTR_variant	Exon 1 of 4	4		ENSP00000511957.1
NPTX1	ENST00000575212.1	n.397C>A		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249088 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460578 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726578

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.608C>A (p.T203N) alteration is located in exon 2 (coding exon 2) of the NPTX1 gene. This alteration results from a C to A substitution at nucleotide position 608, causing the threonine (T) at amino acid position 203 to be replaced by an asparagine (N). 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	0.065
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.26	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.049
Sift	Benign	0.31	T
Sift4G	Benign	0.25	T
Polyphen		0.22	B
Vest4		0.19
MutPred		0.26		Gain of methylation at K200 (P = 0.1249);
MVP		0.17
MPC		0.85
ClinPred		0.059	T
GERP RS		0.40
Varity_R		0.068

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: rs1384003832; hg19: chr17-78449355; COSMIC: COSV99075660; COSMIC: COSV99075660;