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_ModeratePM1PM2PP5_ModerateBP4

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 same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AGR2
NM_006408.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.24

Variant links:

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]

AGR2 links:

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ACMG classification

Classification made for transcript

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 turn (size 2) in uniprot entity AGR2_HUMAN there are 4 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	UniProt
AGR2	NM_006408.4 linkuse as main transcript	c.349C>T	p.His117Tyr	missense_variant	6/8	ENST00000419304.7
AGR2	XM_005249581.5 linkuse as main transcript	c.349C>T	p.His117Tyr	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
AGR2	ENST00000419304.7 linkuse as main transcript	c.349C>T	p.His117Tyr	missense_variant	6/8	1	NM_006408.4	P1
AGR2	ENST00000401412.5 linkuse as main transcript	c.349C>T	p.His117Tyr	missense_variant	6/7	2
AGR2	ENST00000412973.1 linkuse as main transcript	c.349C>T	p.His117Tyr	missense_variant	7/7	5
AGR2	ENST00000450569.5 linkuse as main transcript	c.139C>T	p.His47Tyr	missense_variant	3/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250930

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135628

show subpopulations

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:

AN:

1461304

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726954

show subpopulations

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

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

LIST_S2

Uncertain

0.91

D;T;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.1

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over