7-16878602-G-T

Variant names:

• chr7-16878602-G-T
• NM_176813.5:c.17C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176813.5(AGR3):​c.17C>A​(p.Ala6Asp) 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 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGR3 NM_176813.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33857983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGR3	NM_176813.5	c.17C>A	p.Ala6Asp	missense_variant	Exon 2 of 8	ENST00000310398.7	NP_789783.1
AGR3	XM_047419928.1	c.17C>A	p.Ala6Asp	missense_variant	Exon 3 of 9		XP_047275884.1
AGR3	XM_011515152.3	c.17C>A	p.Ala6Asp	missense_variant	Exon 2 of 8		XP_011513454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGR3	ENST00000310398.7	c.17C>A	p.Ala6Asp	missense_variant	Exon 2 of 8	1	NM_176813.5	ENSP00000308606.2
AGR3	ENST00000402239.7	c.17C>A	p.Ala6Asp	missense_variant	Exon 2 of 7	2		ENSP00000386016.3
AGR3	ENST00000414935.1	c.43+3342C>A		intron_variant	Intron 1 of 5	3		ENSP00000392818.1
AGR3	ENST00000486448.1	n.74C>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727176

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: 8.99e-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

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17C>A (p.A6D) alteration is located in exon 2 (coding exon 1) of the AGR3 gene. This alteration results from a C to A substitution at nucleotide position 17, causing the alanine (A) at amino acid position 6 to be replaced by an aspartic acid (D). 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	Benign	0.25
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.5
DANN	Benign	0.85
DEOGEN2	Benign	0.090	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.20
Sift	Benign	0.065	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.079	B;.
Vest4		0.62
MutPred		0.35		Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);
MVP		0.13
MPC		0.0032
ClinPred		0.14	T
GERP RS		1.8
Varity_R		0.085
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr7-16918226;