rs61757459

Variant names:

• chr14-94497767-G-A
• rs61757459
• NM_001382267.1:c.631C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 4.32
• Publications: 19 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: 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 VariationId is 2574603.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.631C>T	p.Arg211*	stop_gained	Exon 2 of 5	NP_001369196.1	Q8IW75
	SERPINA12	NM_001304461.2		c.631C>T	p.Arg211*	stop_gained	Exon 2 of 5	NP_001291390.1	Q8IW75
	SERPINA12	NM_173850.4		c.631C>T	p.Arg211*	stop_gained	Exon 3 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.631C>T	p.Arg211*	stop_gained	Exon 2 of 5	ENSP00000503935.1	Q8IW75
	SERPINA12	ENST00000341228.2	TSL:1	c.631C>T	p.Arg211*	stop_gained	Exon 3 of 6	ENSP00000342109.2	Q8IW75
	SERPINA12	ENST00000556881.5	TSL:1	c.631C>T	p.Arg211*	stop_gained	Exon 2 of 5	ENSP00000451738.1	Q8IW75

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

GnomAD2 exomes AF: 0.00510 AC: 1235 AN: 242086 AF XY: 0.00498

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.: 53 Cov.: 32 AF XY: 0.00706 AC XY: 5082 AN XY: 719408

African (AFR) AF: 0.00119 AC: 39 AN: 32692

American (AMR) AF: 0.00249 AC: 106 AN: 42538

Ashkenazi Jewish (ASJ) AF: 0.000352 AC: 9 AN: 25596

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39580

South Asian (SAS) AF: 0.000810 AC: 68 AN: 83910

European-Finnish (FIN) AF: 0.0119 AC: 630 AN: 53092

Middle Eastern (MID) AF: 0.00247 AC: 14 AN: 5674

European-Non Finnish (NFE) AF: 0.00860 AC: 9508 AN: 1105806

Other (OTH) AF: 0.00509 AC: 304 AN: 59768

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

African (AFR) AF: 0.00116 AC: 48 AN: 41546

American (AMR) AF: 0.00203 AC: 31 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.0109 AC: 115 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00784 AC: 533 AN: 68006

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00630 Hom.: 9

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary palmoplantar keratoderma, Gamborg-Nielsen type (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.3
Vest4		0.52
GERP RS		5.4
Mutation Taster		=175/25	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs61757459; hg19: chr14-94964104; COSMIC: COSV57941976;