3-167465653-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006217.6(SERPINI2):c.499T>A(p.Ser167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,608,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: SERPINI2 NM_006217.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

Genes affected

SERPINI2 (HGNC:8945): (serpin family I member 2) The gene encodes a member of a family of proteins that acts as inhibitors of serine proteases. These proteins function in the regulation of a variety of physiological processes, including coagulation, fibrinolysis, development, malignancy, and inflammation. Expression of the encoded protein may be downregulated during pancreatic carcinogenesis. Alternative splicing results in multiple transcript variants for this gene. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.149337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI2	NM_006217.6	c.499T>A	p.Ser167Thr	missense_variant	4/9	ENST00000264677.9
SERPINI2	NM_001012303.3	c.499T>A	p.Ser167Thr	missense_variant	5/10
SERPINI2	NM_001394327.1	c.499T>A	p.Ser167Thr	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI2	ENST00000264677.9	c.499T>A	p.Ser167Thr	missense_variant	4/9	1	NM_006217.6	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000257 AC: 62 AN: 241572 Hom.: 0 AF XY: 0.000243 AC XY: 32 AN XY: 131510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000916

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000333 AC: 485 AN: 1456504 Hom.: 0 Cov.: 32 AF XY: 0.000346 AC XY: 251 AN XY: 724586

Gnomad4 AFR exome AF: 0.0000607

Gnomad4 AMR exome AF: 0.000139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000532 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000764

EpiControl AF: 0.000652

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

May 31, 2022

The c.499T>A (p.S167T) alteration is located in exon 4 (coding exon 3) of the SERPINI2 gene. This alteration results from a T to A substitution at nucleotide position 499, causing the serine (S) at amino acid position 167 to be replaced by a threonine (T). 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	0.078
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;T;T;T;.;T
Eigen	Benign	-0.014
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.68	T;T;.;.;.;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.2	M;.;M;M;M;.;.
MutationTaster	Benign	0.65	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;.;N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.090	T;.;T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;.
Polyphen		0.32	B;.;B;B;B;.;.
Vest4		0.32
MVP		0.71
MPC		0.18
ClinPred		0.088	T
GERP RS		4.5
Varity_R		0.24
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200591704; hg19: chr3-167183441;