7-16873820-C-A

Variant names:

• chr7-16873820-C-A
• NM_176813.5:c.133G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_176813.5(AGR3):​c.133G>T​(p.Val45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,722 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V45G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGR3 NM_176813.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.890

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGR3	NM_176813.5	c.133G>T	p.Val45Leu	missense_variant	Exon 3 of 8	ENST00000310398.7	NP_789783.1
AGR3	XM_047419928.1	c.133G>T	p.Val45Leu	missense_variant	Exon 4 of 9		XP_047275884.1
AGR3	XM_011515152.3	c.133G>T	p.Val45Leu	missense_variant	Exon 3 of 8		XP_011513454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGR3	ENST00000310398.7	c.133G>T	p.Val45Leu	missense_variant	Exon 3 of 8	1	NM_176813.5	ENSP00000308606.2
AGR3	ENST00000402239.7	c.133G>T	p.Val45Leu	missense_variant	Exon 3 of 7	2		ENSP00000386016.3
AGR3	ENST00000414935.1	c.67G>T	p.Val23Leu	missense_variant	Exon 2 of 6	3		ENSP00000392818.1
AGR3	ENST00000486448.1	n.190G>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460722 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726696

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0044	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.081
Sift	Benign	0.052	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.014	B;.
Vest4		0.61
MutPred		0.35		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.26
MPC		0.0040
ClinPred		0.75	D
GERP RS		3.3
Varity_R		0.41
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr7-16913444;