7-16797667-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_006408.4(AGR2):c.358C>A(p.Pro120Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGR2 NM_006408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

Genes affected

AGR2 (HGNC:328): (anterior gradient 2, protein disulphide isomerase family member) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, and a C-terminal ER-retention sequence. This protein plays a role in cell migration, cellular transformation and metastasis and is as a p53 inhibitor. As an ER-localized molecular chaperone, it plays a role in the folding, trafficking, and assembly of cysteine-rich transmembrane receptors and the cysteine-rich intestinal gylcoprotein mucin. This gene has been implicated in inflammatory bowel disease and cancer progression. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Anterior gradient protein 2 homolog (size 154) in uniprot entity AGR2_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_006408.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGR2	NM_006408.4	c.358C>A	p.Pro120Thr	missense_variant	6/8	ENST00000419304.7
AGR2	XM_005249581.5	c.358C>A	p.Pro120Thr	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGR2	ENST00000419304.7	c.358C>A	p.Pro120Thr	missense_variant	6/8	1	NM_006408.4	P1
AGR2	ENST00000401412.5	c.358C>A	p.Pro120Thr	missense_variant	6/7	2
AGR2	ENST00000412973.1	c.358C>A	p.Pro120Thr	missense_variant	7/7	5
AGR2	ENST00000450569.5	c.148C>A	p.Pro50Thr	missense_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461606 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000642

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

Dec 22, 2023

The c.358C>A (p.P120T) alteration is located in exon 6 (coding exon 5) of the AGR2 gene. This alteration results from a C to A substitution at nucleotide position 358, causing the proline (P) at amino acid position 120 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.2	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.9	D;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.037	D;D;D;.
Polyphen		0.0020	B;.;.;.
Vest4		0.87
MutPred		0.63		Loss of disorder (P = 0.1164);.;Loss of disorder (P = 0.1164);Loss of disorder (P = 0.1164);
MVP		0.50
MPC		0.73
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.72
gMVP		0.49

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: rs1354569215; hg19: chr7-16837291;