rs61757459

Positions:

• chr14-94497767-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001382267.1(SERPINA12):​c.631C>T​(p.Arg211Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00714 in 1,600,876 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (53 hom.)
• Consequence: SERPINA12 NM_001382267.1 stop_gained
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 4.32

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 14-94497767-G-A is Benign according to our data. Variant chr14-94497767-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2574603.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA12	NM_001382267.1	c.631C>T	p.Arg211Ter	stop_gained	2/5	ENST00000677451.1
SERPINA12	NM_001304461.2	c.631C>T	p.Arg211Ter	stop_gained	2/5
SERPINA12	NM_173850.4	c.631C>T	p.Arg211Ter	stop_gained	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA12	ENST00000677451.1	c.631C>T	p.Arg211Ter	stop_gained	2/5		NM_001382267.1	P1
SERPINA12	ENST00000341228.2	c.631C>T	p.Arg211Ter	stop_gained	3/6	1		P1
SERPINA12	ENST00000556881.5	c.631C>T	p.Arg211Ter	stop_gained	2/5	1		P1

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152102 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00784

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00510 AC: 1235 AN: 242086 Hom.: 5 AF XY: 0.00498 AC XY: 651 AN XY: 130694

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.000211

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000462

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00750

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00737 AC: 10680 AN: 1448656 Hom.: 53 Cov.: 32 AF XY: 0.00706 AC XY: 5082 AN XY: 719408

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.000352

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000810

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.00860

Gnomad4 OTH exome AF: 0.00509

GnomAD4 genome AF: 0.00495 AC: 753 AN: 152220 Hom.: 5 Cov.: 32 AF XY: 0.00453 AC XY: 337 AN XY: 74402

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.00784

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00688 Hom.: 7

Bravo AF: 0.00468

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00526 AC: 638

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary palmoplantar keratoderma, Gamborg-Nielsen type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Institute for Human Genetics, University Medical Center Freiburg

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

SERPINA12: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A
Vest4		0.52
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61757459; hg19: chr14-94964104; COSMIC: COSV57941976;