16-20369596-T-G

Variant summary

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

The NM_174924.2(PDILT):c.1012A>C(p.Ile338Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDILT NM_174924.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

Genes affected

PDILT (HGNC:27338): (protein disulfide isomerase like, testis expressed) 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 has an N-terminal ER-signal sequence, two thioredoxin (TRX) domains with non-classical Ser-Lys-Gln-Ser and Ser-Lys-Lys-Cys motifs, respectively, two TRX-like domains, and a C-terminal ER-retention sequence. The protein lacks oxidoreductase activity in vitro and probably functions as a chaperone. This gene's expression appears to be limited to the testis. [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/exons	MANE	UniProt
PDILT	NM_174924.2	c.1012A>C	p.Ile338Leu	missense_variant	8/12	ENST00000302451.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDILT	ENST00000302451.9	c.1012A>C	p.Ile338Leu	missense_variant	8/12	1	NM_174924.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.1012A>C (p.I338L) alteration is located in exon 8 (coding exon 7) of the PDILT gene. This alteration results from a A to C substitution at nucleotide position 1012, causing the isoleucine (I) at amino acid position 338 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Benign	0.84
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.58	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Uncertain	0.050	T
Polyphen		0.51	P
Vest4		0.67
MutPred		0.54		Gain of catalytic residue at I338 (P = 0.0025);
MVP		0.45
MPC		0.34
ClinPred		0.54	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.59

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: chr16-20380918;