10-127552592-G-C

Variant names:

• chr10-127552592-G-C
• rs4751440
• NM_001030013.2:c.223G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001030013.2(NPS):​c.223G>C​(p.Val75Leu) variant causes a missense change. The variant allele was found at a frequency of 0.118 in 1,612,608 control chromosomes in the GnomAD database, including 12,592 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.088 (763 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11829 hom.)
• Consequence: NPS NM_001030013.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.79
• Publications: 17 publications found

Genes affected

NPS (HGNC:33940): (neuropeptide S) Predicted to be involved in positive regulation of GABAergic synaptic transmission; positive regulation of action potential; and positive regulation of glutamatergic synaptic transmission. Predicted to act upstream of or within visual learning. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027403831).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001030013.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPS	NM_001030013.2	MANE Select	c.223G>C	p.Val75Leu	missense	Exon 3 of 3	NP_001025184.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPS	ENST00000398023.3	TSL:5 MANE Select	c.223G>C	p.Val75Leu	missense	Exon 3 of 3	ENSP00000381105.2

Frequencies

GnomAD3 genomes AF: 0.0881 AC: 13397 AN: 152114 Hom.: 763 Cov.: 33

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.0982

GnomAD2 exomes AF: 0.0936 AC: 23327 AN: 249186 AF XY: 0.0955

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.0622

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.121 AC: 177243 AN: 1460376 Hom.: 11829 Cov.: 31 AF XY: 0.120 AC XY: 87127 AN XY: 726576

African (AFR) AF: 0.0190 AC: 637 AN: 33470

American (AMR) AF: 0.0643 AC: 2874 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2794 AN: 26126

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39686

South Asian (SAS) AF: 0.0468 AC: 4032 AN: 86222

European-Finnish (FIN) AF: 0.0895 AC: 4781 AN: 53402

Middle Eastern (MID) AF: 0.104 AC: 597 AN: 5764

European-Non Finnish (NFE) AF: 0.140 AC: 155050 AN: 1110644

Other (OTH) AF: 0.107 AC: 6472 AN: 60354

GnomAD4 genome AF: 0.0880 AC: 13391 AN: 152232 Hom.: 763 Cov.: 33 AF XY: 0.0839 AC XY: 6248 AN XY: 74430

African (AFR) AF: 0.0245 AC: 1018 AN: 41540

American (AMR) AF: 0.0784 AC: 1198 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 380 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0437 AC: 211 AN: 4828

European-Finnish (FIN) AF: 0.0917 AC: 973 AN: 10608

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9242 AN: 68014

Other (OTH) AF: 0.0967 AC: 204 AN: 2110

Alfa AF: 0.110 Hom.: 662

Bravo AF: 0.0848

TwinsUK AF: 0.145 AC: 539

ALSPAC AF: 0.140 AC: 539

ESP6500AA AF: 0.0220 AC: 82

ESP6500EA AF: 0.140 AC: 1145

ExAC AF: 0.0956 AC: 11548

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.146

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.97	T
PhyloP100		4.8
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.27
MPC		0.011
ClinPred		0.029	T
GERP RS		5.5
Varity_R		0.68
gMVP		0.055
Mutation Taster		=84/16	polymorphism (auto)

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: rs4751440; hg19: chr10-129350856; COSMIC: COSV67691017;