7-16797676-G-A

Position:

• chr7-16797676-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PS1_Moderate PM1 PM2 PP5_Moderate BP4

The NM_006408.4(AGR2):​c.349C>T​(p.His117Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGR2 NM_006408.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.24

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_006408.4 (AGR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Anterior gradient protein 2 homolog (size 154) in uniprot entity AGR2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006408.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-16797676-G-A is Pathogenic according to our data. Variant chr7-16797676-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2443886.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-16797676-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-16797676-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3345108). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGR2	NM_006408.4	c.349C>T	p.His117Tyr	missense_variant	6/8	ENST00000419304.7	NP_006399.1
AGR2	XM_005249581.5	c.349C>T	p.His117Tyr	missense_variant	6/8		XP_005249638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGR2	ENST00000419304.7	c.349C>T	p.His117Tyr	missense_variant	6/8	1	NM_006408.4	ENSP00000391490.2
AGR2	ENST00000401412.5	c.349C>T	p.His117Tyr	missense_variant	6/7	2		ENSP00000386025.1
AGR2	ENST00000412973.1	c.349C>T	p.His117Tyr	missense_variant	7/7	5		ENSP00000411969.1
AGR2	ENST00000450569.5	c.139C>T	p.His47Tyr	missense_variant	3/5	5		ENSP00000414806.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250930 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461304 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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 Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Respiratory infections, recurrent, and failure to thrive with or without diarrhea Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 31, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;T;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;.
Polyphen		0.95	P;.;.;.
Vest4		0.39
MutPred		0.26		Gain of phosphorylation at H117 (P = 0.018);.;Gain of phosphorylation at H117 (P = 0.018);Gain of phosphorylation at H117 (P = 0.018);
MVP		0.49
MPC		0.59
ClinPred		0.76	D
GERP RS		6.0
Varity_R		0.47
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs780638101; hg19: chr7-16837300;