14-94489739-G-A

Position:

• chr14-94489739-G-A

Variant summary

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

The NM_001382267.1(SERPINA12):​c.934C>T​(p.His312Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000021 (0 hom.)
• Consequence: SERPINA12 NM_001382267.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.268

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]

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=0.15859446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA12	NM_001382267.1	c.934C>T	p.His312Tyr	missense_variant	4/5	ENST00000677451.1
SERPINA12	NM_001304461.2	c.934C>T	p.His312Tyr	missense_variant	4/5
SERPINA12	NM_173850.4	c.934C>T	p.His312Tyr	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA12	ENST00000677451.1	c.934C>T	p.His312Tyr	missense_variant	4/5		NM_001382267.1	P1
SERPINA12	ENST00000341228.2	c.934C>T	p.His312Tyr	missense_variant	5/6	1		P1
SERPINA12	ENST00000556881.5	c.934C>T	p.His312Tyr	missense_variant	4/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Sep 22, 2023

The c.934C>T (p.H312Y) alteration is located in exon 5 (coding exon 3) of the SERPINA12 gene. This alteration results from a C to T substitution at nucleotide position 934, causing the histidine (H) at amino acid position 312 to be replaced by a tyrosine (Y). 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	0.090
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.1
DANN	Benign	0.93
DEOGEN2	Benign	0.094	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0069	N
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.23
Sift	Benign	0.21	T;T
Sift4G	Benign	0.078	T;T
Polyphen		0.0020	B;B
Vest4		0.19
MutPred		0.67		Gain of catalytic residue at F317 (P = 0.0019);Gain of catalytic residue at F317 (P = 0.0019);
MVP		0.030
MPC		0.022
ClinPred		0.067	T
GERP RS		-5.0
Varity_R		0.23
gMVP		0.51

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: rs1330519693; hg19: chr14-94956076;