19-42730000-C-G

Position:

• chr19-42730000-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021016.4(PSG3):​c.766G>C​(p.Asp256His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSG3 NM_021016.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.900

Genes affected

PSG3 (HGNC:9520): (pregnancy specific beta-1-glycoprotein 3) The human pregnancy-specific glycoproteins (PSGs) are a family of proteins that are synthesized in large amounts by placental trophoblasts and released into the maternal circulation during pregnancy. Molecular cloning and analysis of several PSG genes has indicated that the PSGs form a subgroup of the carcinoembryonic antigen (CEA) gene family, which belongs to the immunoglobulin superfamily of genes. Members of the CEA family consist of a single N domain, with structural similarity to the immunoglobulin variable domains, followed by a variable number of immunoglobulin constant-like A and/or B domains. Most PSGs have an arg-gly-asp (RGD) motif, which has been shown to function as an adhesion recognition signal for several integrins, in the N-terminal domain (summary by Teglund et al., 1994 [PubMed 7851896]). For additional general information about the PSG gene family, see PSG1 (MIM 176390).[supplied by OMIM, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19727752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSG3	NM_021016.4	c.766G>C	p.Asp256His	missense_variant	4/7	ENST00000327495.10	NP_066296.2
PSG3	XM_011527126.3	c.776-623G>C		intron_variant			XP_011525428.1
PSG3	XM_011527127.3	c.775+2784G>C		intron_variant			XP_011525429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSG3	ENST00000327495.10	c.766G>C	p.Asp256His	missense_variant	4/7	1	NM_021016.4	ENSP00000332215.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460166 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 726410

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.766G>C (p.D256H) alteration is located in exon 4 (coding exon 4) of the PSG3 gene. This alteration results from a G to C substitution at nucleotide position 766, causing the aspartic acid (D) at amino acid position 256 to be replaced by a histidine (H). 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	Benign	0.33
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.7
DANN	Benign	0.93
DEOGEN2	Benign	0.040	T;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.00051	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;.;M
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;.;.
REVEL	Benign	0.066
Sift	Uncertain	0.0070	D;.;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.33
MutPred		0.33		Loss of ubiquitination at K255 (P = 0.073);Loss of ubiquitination at K255 (P = 0.073);Loss of ubiquitination at K255 (P = 0.073);
MVP		0.31
MPC		0.010
ClinPred		0.60	D
GERP RS		-0.20
Varity_R		0.091
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-43234152;