chr19-43258910-A-G

Variant names:

• chr19-43258910-A-G
• NM_002784.5:c.935T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002784.5(PSG9):​c.935T>C​(p.Ile312Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,443,262 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000028 (1 hom.)
• Consequence: PSG9 NM_002784.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.627
• Publications: 0 publications found

Genes affected

PSG9 (HGNC:9526): (pregnancy specific beta-1-glycoprotein 9) The protein encoded by this gene is a member of the pregnancy-specific glycoprotein (PSG) family. This protein family and the closely related carcinoembryonic antigen cell adhesion molecule (CEACAM) gene family are both members of the immunoglobulin superfamily, and are organized as a large gene cluster. This protein is thought to inhibit platelet-fibrinogen interactions. Several studies suggest that reduced serum concentrations of PSGs are associated with fetal growth restrictions, while up-regulation of this gene has been observed in colorectal cancers. Several pseudogenes of this gene are found on chromosome 19. Alternative splicing results in multiple transcript variants that encode multiple protein isoforms. [provided by RefSeq, Sep 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3099376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSG9	NM_002784.5	c.935T>C	p.Ile312Thr	missense_variant	Exon 4 of 6	ENST00000270077.8	NP_002775.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSG9	ENST00000270077.8	c.935T>C	p.Ile312Thr	missense_variant	Exon 4 of 6	1	NM_002784.5	ENSP00000270077.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1443262 Hom.: 1 Cov.: 34 AF XY: 0.00000278 AC XY: 2 AN XY: 718208

African (AFR) AF: 0.0000623 AC: 2 AN: 32082

American (AMR) AF: 0.00 AC: 0 AN: 43844

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 33324

South Asian (SAS) AF: 0.00 AC: 0 AN: 85252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4182

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106388

Other (OTH) AF: 0.00 AC: 0 AN: 59260

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.935T>C (p.I312T) alteration is located in exon 4 (coding exon 4) of the PSG9 gene. This alteration results from a T to C substitution at nucleotide position 935, causing the isoleucine (I) at amino acid position 312 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.79
DANN	Benign	0.38
DEOGEN2	Benign	0.035	T;T;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.00042	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;L;.
PhyloP100		-0.63
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	.;.;N;N
REVEL	Benign	0.090
Sift	Benign	0.046	.;.;D;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.88, 0.99	.;.;P;D
Vest4		0.21
MutPred		0.69		.;Gain of phosphorylation at I312 (P = 0.0213);Gain of phosphorylation at I312 (P = 0.0213);.;
MVP		0.092
MPC		0.020
ClinPred		0.31	T
GERP RS		-2.3
Varity_R		0.058
gMVP		0.14
Mutation Taster		=98/2	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

hg19: chr19-43763062;