NM_001382267.1:c.952G>T

Variant names:

• chr14-94489721-C-A
• rs773146990
• NM_001382267.1:c.952G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001382267.1(SERPINA12):​c.952G>T​(p.Asp318Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D318N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINA12 NM_001382267.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.499
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

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.952G>T	p.Asp318Tyr	missense	Exon 4 of 5	NP_001369196.1	Q8IW75
	SERPINA12	NM_001304461.2		c.952G>T	p.Asp318Tyr	missense	Exon 4 of 5	NP_001291390.1	Q8IW75
	SERPINA12	NM_173850.4		c.952G>T	p.Asp318Tyr	missense	Exon 5 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.952G>T	p.Asp318Tyr	missense	Exon 4 of 5	ENSP00000503935.1	Q8IW75
	SERPINA12	ENST00000341228.2	TSL:1	c.952G>T	p.Asp318Tyr	missense	Exon 5 of 6	ENSP00000342109.2	Q8IW75
	SERPINA12	ENST00000556881.5	TSL:1	c.952G>T	p.Asp318Tyr	missense	Exon 4 of 5	ENSP00000451738.1	Q8IW75

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	14
DANN	Uncertain	0.97
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.50
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.60		Gain of catalytic residue at T314 (P = 6e-04)
MVP		0.60
MPC		0.17
ClinPred		0.93	D
GERP RS		-2.3
Varity_R		0.77
gMVP		0.68
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs773146990; hg19: chr14-94956058;