NM_207172.2:c.290C>T

Variant names:

• chr7-34778471-C-T
• rs1562720134
• NM_207172.2:c.290C>T
• NPSR1 p.Thr97Ile

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBS2

The NM_207172.2(NPSR1):c.290C>T (p.Thr97Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000627 (AC=10) in the gnomAD database across 1,595,424 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NPSR1 NM_207172.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75
• Publications: 0 publications found

Genes affected

NPSR1 (HGNC:23631): (neuropeptide S receptor 1) This gene encodes a member of the vasopressin/oxytocin subfamily of G protein-coupled receptors. The encoded membrane protein acts as a receptor for neuropeptide S and affects a variety of cellular processes through its signaling. Increased expression of this gene in ciliated cells of the respiratory epithelium and in bronchial smooth muscle cells is associated with asthma. Polymorphisms in this gene have also been associated with asthma susceptibility, panic disorders, inflammatory bowel disease, and rheumatoid arthritis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

NPSR1 Gene-Disease associations (from GenCC):

• asthma-related traits, susceptibility to, 2

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

NPSR1-AS1 (HGNC:22128): (NPSR1 antisense RNA 1) This gene is located within a region that has been associated with asthma susceptibility. The locus is considered non-protein-coding based on lack of protein homology and a lack of experimental support for an encoded protein. Three alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, May 2010]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000655 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 10 (pure AD gene, not AR).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_207172.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPSR1	NM_207172.2	MANE Select	c.290C>T	p.Thr97Ile	missense	Exon 3 of 9	NP_997055.1	Q6W5P4-1
	NPSR1	NM_001300935.2		c.290C>T	p.Thr97Ile	missense	Exon 3 of 10	NP_001287864.1	Q6W5P4-3
	NPSR1	NM_207173.2		c.290C>T	p.Thr97Ile	missense	Exon 3 of 9	NP_997056.1	Q6W5P4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPSR1	ENST00000360581.6	TSL:1 MANE Select	c.290C>T	p.Thr97Ile	missense	Exon 3 of 9	ENSP00000353788.1	Q6W5P4-1
	NPSR1	ENST00000381539.3	TSL:1	c.290C>T	p.Thr97Ile	missense	Exon 3 of 10	ENSP00000370950.3	Q6W5P4-3
	NPSR1	ENST00000359791.5	TSL:1	c.290C>T	p.Thr97Ile	missense	Exon 3 of 9	ENSP00000352839.1	Q6W5P4-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152140	Cov:32
GnomAD2 exomes	AF: 0.00000404	AC:1	Hom:	AN:247356	Cov:
GnomAD4 exome	AF: 0.00000624	AC:9	Hom:0	AN:1443284	Cov:25
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152140	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	112668	0.0000158	3	189604

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	28
AlphaMissense	Pathogenic	-	0.76
BayesDel_addAF	Pathogenic	D	0.25
BayesDel_noAF	Uncertain	-	0.12
CADD	Pathogenic	-	26
DANN	Uncertain	-	1.0
DEOGEN2	Benign	T	0.048
Eigen	Uncertain	-	0.36
Eigen_PC	Uncertain	-	0.41
FATHMM_MKL	Uncertain	D	0.85
FuncVEP CTI	Pathogenic	-	0.55
GPN-Star LLR	N/A	-	-2.9
GPN-Star score	N/A	-	2.9
LIST_S2	Uncertain	D	0.90
M_CAP	Benign	D	0.037
MetaRNN	Uncertain	D	0.72
MetaSVM	Benign	T	-0.44
Mutation Taster	N/A	polymorphism	74/26
MutationAssessor	Benign	L	0.90
PhyloP100	Uncertain	-	4.8
popEVE	Benign	-	-3.3
PrimateAI	Uncertain	T	0.74
PROVEAN	Benign	N	0.92
REVEL	Uncertain	-	0.32
Sift	Uncertain	D	0.013
Sift4G	Uncertain	D	0.0090
Varity_R	N/A	-	0.13
VESM-3B	Benign	-	-8.2

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.050
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.050

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1562720134;

hg19: chr7-34818083;

COSMIC: COSV62197893;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar