rs325465

Variant names:

• chr7-34811812-A-C
• rs325465
• NM_207172.2:c.427A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-34811812-A-C
• chr7-34811812-A-G
• chr7-34811812-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_207172.2(NPSR1):​c.427A>C​(p.Ser143Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S143G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPSR1 NM_207172.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61
• Publications: 10 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-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]

ENSG00000300889 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207172.2. 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
	NPSR1	NM_207172.2	MANE Select	c.427A>C	p.Ser143Arg	missense	Exon 4 of 9	NP_997055.1	Q6W5P4-1
	NPSR1	NM_001300935.2		c.427A>C	p.Ser143Arg	missense	Exon 4 of 10	NP_001287864.1	Q6W5P4-3
	NPSR1	NM_207173.2		c.427A>C	p.Ser143Arg	missense	Exon 4 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.427A>C	p.Ser143Arg	missense	Exon 4 of 9	ENSP00000353788.1	Q6W5P4-1
	NPSR1	ENST00000381539.3	TSL:1	c.427A>C	p.Ser143Arg	missense	Exon 4 of 10	ENSP00000370950.3	Q6W5P4-3
	NPSR1	ENST00000359791.5	TSL:1	c.427A>C	p.Ser143Arg	missense	Exon 4 of 9	ENSP00000352839.1	Q6W5P4-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250864 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461360 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727022

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.84		Gain of catalytic residue at S143 (P = 0.1025)
MVP		0.97
MPC		0.041
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.98
gMVP		0.97
Mutation Taster		=23/77	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: rs325465; hg19: chr7-34851424;