dbSNP rs61757459: SERPINA12:p.Arg211* (chr14-94497767-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_001382267.1(SERPINA12):c.631C>T(p.Arg211*) 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

Scores

Clinical Significance

Likely benign criteria provided, single submitter P:1B:1

Conservation

PhyloP100: 4.32

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

hereditary palmoplantar keratoderma, Gamborg-Nielsen type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SERPINA12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
SERPINA12	NM_001382267.1 link	c.631C>T	p.Arg211*	stop_gained	Exon 2 of 5	ENST00000677451.1	NP_001369196.1
SERPINA12	NM_001304461.2 link	c.631C>T	p.Arg211*	stop_gained	Exon 2 of 5		NP_001291390.1	Q8IW75
SERPINA12	NM_173850.4 link	c.631C>T	p.Arg211*	stop_gained	Exon 3 of 6		NP_776249.1	Q8IW75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINA12	ENST00000677451.1 link	c.631C>T	p.Arg211*	stop_gained	Exon 2 of 5		NM_001382267.1	ENSP00000503935.1	Q8IW75
SERPINA12	ENST00000341228.2 link	c.631C>T	p.Arg211*	stop_gained	Exon 3 of 6	1		ENSP00000342109.2	Q8IW75
SERPINA12	ENST00000556881.5 link	c.631C>T	p.Arg211*	stop_gained	Exon 2 of 5	1		ENSP00000451738.1	Q8IW75

Frequencies

GnomAD3 genomes

AF:

0.00495

AC:

753

AN:

152102

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00510

AC:

1235

AN:

242086

AF XY:

0.00498

show subpopulations

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 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.:

Cov.:

AF XY:

0.00706

AC XY:

5082

AN XY:

719408

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

32692

American (AMR)

AF:

0.00249

AC:

106

AN:

42538

Ashkenazi Jewish (ASJ)

AF:

0.000352

AC:

AN:

25596

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39580

South Asian (SAS)

AF:

0.000810

AC:

AN:

83910

European-Finnish (FIN)

AF:

0.0119

AC:

630

AN:

53092

Middle Eastern (MID)

AF:

0.00247

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00860

AC:

9508

AN:

1105806

Other (OTH)

AF:

0.00509

AC:

304

AN:

59768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

532

1064

1596

2128

2660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00495

AC:

753

AN:

152220

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

337

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41546

American (AMR)

AF:

0.00203

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0109

AC:

115

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00784

AC:

533

AN:

68006

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00630

Hom.:

Bravo

AF:

0.00468

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00526

AC:

638

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary palmoplantar keratoderma, Gamborg-Nielsen type

Pathogenic:1

Institute for Human Genetics, University Medical Center Freiburg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SERPINA12: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.89

PhyloP100

4.3

Vest4

0.52

GERP RS

5.4

Mutation Taster

=175/25

disease causing (fs/PTC)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over