1-167063732-G-A

Variant names:

• chr1-167063732-G-A
• NM_005814.3:c.421C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005814.3(GPA33):​c.421C>T​(p.Pro141Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPA33 NM_005814.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30

Genes affected

GPA33 (HGNC:4445): (glycoprotein A33) The glycoprotein encoded by this gene is a cell surface antigen that is expressed in greater than 95% of human colon cancers. The open reading frame encodes a 319-amino acid polypeptide having a putative secretory signal sequence and 3 potential glycosylation sites. The predicted mature protein has a 213-amino acid extracellular region, a single transmembrane domain, and a 62-amino acid intracellular tail. The sequence of the extracellular region contains 2 domains characteristic of the CD2 subgroup of the immunoglobulin (Ig) superfamily. [provided by RefSeq, Jul 2008]

LOC105371600 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPA33	NM_005814.3	c.421C>T	p.Pro141Ser	missense_variant	Exon 4 of 7	ENST00000367868.4	NP_005805.1
GPA33	XM_017000005.2	c.97C>T	p.Pro33Ser	missense_variant	Exon 5 of 8		XP_016855494.1
GPA33	XM_047424480.1	c.97C>T	p.Pro33Ser	missense_variant	Exon 6 of 9		XP_047280436.1
LOC105371600	XR_922249.3	n.545+615G>A		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPA33	ENST00000367868.4	c.421C>T	p.Pro141Ser	missense_variant	Exon 4 of 7	1	NM_005814.3	ENSP00000356842.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.421C>T (p.P141S) alteration is located in exon 4 (coding exon 4) of the GPA33 gene. This alteration results from a C to T substitution at nucleotide position 421, causing the proline (P) at amino acid position 141 to be replaced by a serine (S). 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	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-7.0	D;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.015	D;.
Polyphen		1.0	D;.
Vest4		0.65
MutPred		0.63		Loss of glycosylation at P141 (P = 0.0504);.;
MVP		0.75
MPC		0.41
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.53
gMVP		0.87

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: chr1-167032969;