Genetic Variant SERPINA12:p.Glu351Val (chr14-94489621-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001382267.1(SERPINA12):c.1052A>T(p.Glu351Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000186 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SERPINA12
NM_001382267.1 missense, splice_region

Scores

Splicing: ADA: 0.7238

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

Variant links:

Genes affected

SERPINA12 (HGNC:18359): (serpin family A member 12) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to act upstream of or within negative regulation of gluconeogenesis; positive regulation of signal transduction; and regulation of lipid metabolic process. Predicted to be located in plasma membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SERPINA12 links:

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ACMG classification

Classification made for transcript

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
SERPINA12	NM_001382267.1 link	c.1052A>T	p.Glu351Val	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000677451.1	NP_001369196.1
SERPINA12	NM_001304461.2 link	c.1052A>T	p.Glu351Val	missense_variant, splice_region_variant	Exon 4 of 5		NP_001291390.1	Q8IW75
SERPINA12	NM_173850.4 link	c.1052A>T	p.Glu351Val	missense_variant, splice_region_variant	Exon 5 of 6		NP_776249.1	Q8IW75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINA12	ENST00000677451.1 link	c.1052A>T	p.Glu351Val	missense_variant, splice_region_variant	Exon 4 of 5		NM_001382267.1	ENSP00000503935.1	Q8IW75
SERPINA12	ENST00000341228.2 link	c.1052A>T	p.Glu351Val	missense_variant, splice_region_variant	Exon 5 of 6	1		ENSP00000342109.2	Q8IW75
SERPINA12	ENST00000556881.5 link	c.1052A>T	p.Glu351Val	missense_variant, splice_region_variant	Exon 4 of 5	1		ENSP00000451738.1	Q8IW75

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1052A>T (p.E351V) alteration is located in exon 5 (coding exon 3) of the SERPINA12 gene. This alteration results from a A to T substitution at nucleotide position 1052, causing the glutamic acid (E) at amino acid position 351 to be replaced by a valine (V). 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

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

T;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.57

.;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.54

P;P

Vest4

0.47

MutPred

0.54

Loss of disorder (P = 0.0112);Loss of disorder (P = 0.0112);

MVP

0.57

MPC

0.13

ClinPred

0.98

GERP RS

4.9

Varity_R

0.50

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.72

dbscSNV1_RF

Benign

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over