7-16797693-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006408.4(AGR2):c.332A>G(p.Tyr111Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGR2 NM_006408.4 missense, splice_region
• Scores: Splicing: ADA: 0.9178
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGR2	NM_006408.4	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/8	ENST00000419304.7
AGR2	XM_005249581.5	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGR2	ENST00000419304.7	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/8	1	NM_006408.4	P1
AGR2	ENST00000401412.5	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	6/7	2
AGR2	ENST00000412973.1	c.332A>G	p.Tyr111Cys	missense_variant, splice_region_variant	7/7	5
AGR2	ENST00000450569.5	c.122A>G	p.Tyr41Cys	missense_variant, splice_region_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460598 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726568

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: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Respiratory infections, recurrent, and failure to thrive with or without diarrhea Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.020	D;T;T;.
Polyphen		1.0	D;.;.;.
Vest4		0.79
MutPred		0.43		Gain of catalytic residue at T113 (P = 0.0575);.;Gain of catalytic residue at T113 (P = 0.0575);Gain of catalytic residue at T113 (P = 0.0575);
MVP		0.73
MPC		0.78
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.41
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.040		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: chr7-16837317;