3-167467094-C-A

Variant summary

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

The NM_006217.6(SERPINI2):c.439G>T(p.Ala147Ser) 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 1,461,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINI2 NM_006217.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27066025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI2	NM_006217.6	c.439G>T	p.Ala147Ser	missense_variant	3/9	ENST00000264677.9
SERPINI2	NM_001012303.3	c.439G>T	p.Ala147Ser	missense_variant	4/10
SERPINI2	NM_001394327.1	c.439G>T	p.Ala147Ser	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI2	ENST00000264677.9	c.439G>T	p.Ala147Ser	missense_variant	3/9	1	NM_006217.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250954 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135648

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461122 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

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

Jan 23, 2024

The c.439G>T (p.A147S) alteration is located in exon 3 (coding exon 2) of the SERPINI2 gene. This alteration results from a G to T substitution at nucleotide position 439, causing the alanine (A) at amino acid position 147 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;T;T;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T;T;.;.;.;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Benign	1.4	L;.;L;L;L;.;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.51	N;.;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.084	T;.;T;T;T;D;D
Sift4G	Benign	0.20	T;T;T;T;T;T;.
Polyphen		0.99	D;.;D;D;D;.;.
Vest4		0.20
MVP		0.85
MPC		0.62
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.18
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs376264822; hg19: chr3-167184882;