7-16861417-C-G

Variant names:

• chr7-16861417-C-G
• rs1340365833
• NM_176813.5:c.334G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_176813.5(AGR3):​c.334G>C​(p.Asp112His) 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: 33)
• Consequence: AGR3 NM_176813.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

Genes affected

AGR3 (HGNC:24167): (anterior gradient 3, 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 gene is expressed in ciliated airway epithelial cells and, in mouse, plays a role in ciliary beat frequency in multiciliated cells. This gene is also over-expressed in breast, ovarian, and prostrate cancers. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGR3	NM_176813.5	c.334G>C	p.Asp112His	missense_variant	Exon 6 of 8	ENST00000310398.7	NP_789783.1
AGR3	XM_047419928.1	c.334G>C	p.Asp112His	missense_variant	Exon 7 of 9		XP_047275884.1
AGR3	XM_011515152.3	c.334G>C	p.Asp112His	missense_variant	Exon 6 of 8		XP_011513454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGR3	ENST00000310398.7	c.334G>C	p.Asp112His	missense_variant	Exon 6 of 8	1	NM_176813.5	ENSP00000308606.2
AGR3	ENST00000402239.7	c.334G>C	p.Asp112His	missense_variant	Exon 6 of 7	2		ENSP00000386016.3
AGR3	ENST00000414935.1	c.268G>C	p.Asp90His	missense_variant	Exon 5 of 6	3		ENSP00000392818.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.334G>C (p.D112H) alteration is located in exon 6 (coding exon 5) of the AGR3 gene. This alteration results from a G to C substitution at nucleotide position 334, causing the aspartic acid (D) at amino acid position 112 to be replaced by a histidine (H). 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	0.92
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.65		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.50
MPC		0.013
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.64

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: rs1340365833; hg19: chr7-16901041;