8-142681405-T-C

Variant names:

• chr8-142681405-T-C
• rs1814631554
• NM_005672.5:c.104T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005672.5(PSCA):​c.104T>C​(p.Leu35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. L35R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PSCA NM_005672.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 0 publications found

Genes affected

PSCA (HGNC:9500): (prostate stem cell antigen) This gene encodes a glycosylphosphatidylinositol-anchored cell membrane glycoprotein. In addition to being highly expressed in the prostate it is also expressed in the bladder, placenta, colon, kidney, and stomach. This gene is up-regulated in a large proportion of prostate cancers and is also detected in cancers of the bladder and pancreas. This gene includes a polymorphism that results in an upstream start codon in some individuals; this polymorphism is thought to be associated with a risk for certain gastric and bladder cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

JRK (HGNC:6199): (Jrk helix-turn-helix protein) This gene encodes a conserved protein that is similar to DNA-binding proteins, such as major centromere autoantigen B (CENPB). Inactivation of the related gene in mice resulted in epileptic seizures. Childhood Absence Epilepsy (CAE) has been mapped to the same chromosomal location (8q24.3) as this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049907863).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005672.5. 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
	PSCA	NM_005672.5	MANE Select	c.104T>C	p.Leu35Pro	missense	Exon 2 of 3	NP_005663.2	O43653
	PSCA	NR_033343.2		n.351T>C		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSCA	ENST00000301258.5	TSL:1 MANE Select	c.104T>C	p.Leu35Pro	missense	Exon 2 of 3	ENSP00000301258.4	O43653
	PSCA	ENST00000918921.1		c.104T>C	p.Leu35Pro	missense	Exon 3 of 4	ENSP00000588980.1
	PSCA	ENST00000966863.1		c.104T>C	p.Leu35Pro	missense	Exon 2 of 3	ENSP00000636922.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441422 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714866

⚠️ 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: 33030

American (AMR) AF: 0.00 AC: 0 AN: 42188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 38706

South Asian (SAS) AF: 0.00 AC: 0 AN: 82618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102428

Other (OTH) AF: 0.00 AC: 0 AN: 59640

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.24
DANN	Benign	0.45
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00067	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.0020
Sift	Benign	0.29	T
Sift4G	Benign	0.27	T
Vest4		0.13
MVP		0.076
MPC		0.018
ClinPred		0.14	T
GERP RS		-4.2
Varity_R		0.054
gMVP		0.54
Mutation Taster		=99/1	polymorphism

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: rs1814631554; hg19: chr8-143762823;