rs9263726

Positions:

• chr6-31138722-G-A
• chr6-31138722-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014068.3(PSORS1C1):​c.110G>A​(p.Arg37His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,608,304 control chromosomes in the GnomAD database, including 13,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1412 hom., cov: 30)
  • Exomes 𝑓: 0.13 (12117 hom.)
• Consequence: PSORS1C1 NM_014068.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.27

Genes affected

PSORS1C1 (HGNC:17202): (psoriasis susceptibility 1 candidate 1) This gene is one of several genes thought to confer susceptibility to psoriasis and systemic sclerosis, located on chromosome 6 near the major histocompatibility complex (MHC) class I region. [provided by RefSeq, Sep 2011]

PSORS1C2 (HGNC:17199): (psoriasis susceptibility 1 candidate 2) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.252429E-4).
• BP6: Variant 6-31138722-G-A is Benign according to our data. Variant chr6-31138722-G-A is described in ClinVar as [Benign]. Clinvar id is 3059106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSORS1C1	NM_014068.3	c.110G>A	p.Arg37His	missense_variant	5/6	ENST00000259881.10
PSORS1C2	NM_014069.3	c.55+250C>T		intron_variant		ENST00000259845.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSORS1C1	ENST00000259881.10	c.110G>A	p.Arg37His	missense_variant	5/6	1	NM_014068.3	P2
PSORS1C2	ENST00000259845.5	c.55+250C>T		intron_variant		1	NM_014069.3	P1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 19928 AN: 146574 Hom.: 1406 Cov.: 30

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0935

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.122

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.115 AC: 27655 AN: 241276 Hom.: 1745 AF XY: 0.114 AC XY: 14990 AN XY: 131098

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0873

Gnomad ASJ exome AF: 0.0908

Gnomad EAS exome AF: 0.0986

Gnomad SAS exome AF: 0.0723

Gnomad FIN exome AF: 0.0994

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.125 AC: 182852 AN: 1461614 Hom.: 12117 Cov.: 52 AF XY: 0.124 AC XY: 89886 AN XY: 727122

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0903

Gnomad4 ASJ exome AF: 0.0829

Gnomad4 EAS exome AF: 0.0466

Gnomad4 SAS exome AF: 0.0737

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.136 AC: 19962 AN: 146690 Hom.: 1412 Cov.: 30 AF XY: 0.134 AC XY: 9565 AN XY: 71480

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0935

Gnomad4 EAS AF: 0.0747

Gnomad4 SAS AF: 0.0703

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.154

Alfa AF: 0.129 Hom.: 2896

Bravo AF: 0.136

TwinsUK AF: 0.126 AC: 468

ALSPAC AF: 0.141 AC: 545

ExAC AF: 0.115 AC: 13808

Asia WGS AF: 0.100 AC: 346 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PSORS1C1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.48
DANN	Benign	0.92
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0069	N
MetaRNN	Benign	0.00093	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.040
MPC		0.58
ClinPred		0.015	T
GERP RS		-4.9
Varity_R		0.019
gMVP		0.011

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: rs9263726; hg19: chr6-31106499; COSMIC: COSV52535056; COSMIC: COSV52535056;