14-94487485-T-C

Variant names:

• chr14-94487485-T-C
• rs1470474112
• NM_001382267.1:c.1063A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001382267.1(SERPINA12):​c.1063A>G​(p.Lys355Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SERPINA12 NM_001382267.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.171
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hereditary palmoplantar keratoderma, Gamborg-Nielsen type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382267.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA12	NM_001382267.1	MANE Select	c.1063A>G	p.Lys355Glu	missense	Exon 5 of 5	NP_001369196.1	Q8IW75
	SERPINA12	NM_001304461.2		c.1063A>G	p.Lys355Glu	missense	Exon 5 of 5	NP_001291390.1	Q8IW75
	SERPINA12	NM_173850.4		c.1063A>G	p.Lys355Glu	missense	Exon 6 of 6	NP_776249.1	Q8IW75

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA12	ENST00000677451.1	MANE Select	c.1063A>G	p.Lys355Glu	missense	Exon 5 of 5	ENSP00000503935.1	Q8IW75
	SERPINA12	ENST00000341228.2	TSL:1	c.1063A>G	p.Lys355Glu	missense	Exon 6 of 6	ENSP00000342109.2	Q8IW75
	SERPINA12	ENST00000556881.5	TSL:1	c.1063A>G	p.Lys355Glu	missense	Exon 5 of 5	ENSP00000451738.1	Q8IW75

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247596 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000137 AC: 2 AN: 1459180 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725752

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.0000452 AC: 2 AN: 44248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110844

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.0028	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.17
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.46
Sift	Benign	0.056	T
Sift4G	Benign	0.070	T
Polyphen		0.75	P
Vest4		0.33
MutPred		0.71		Loss of ubiquitination at K355 (P = 0.021)
MVP		0.48
MPC		0.053
ClinPred		0.39	T
GERP RS		1.9
Varity_R		0.45
gMVP		0.61
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs1470474112; hg19: chr14-94953822;