22-20779572-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000185.4(SERPIND1):c.260G>A(p.Ser87Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,614,212 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0074 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (11 hom.)
• Consequence: SERPIND1 NM_000185.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.67

Genes affected

SERPIND1 (HGNC:4838): (serpin family D member 1) This gene belongs to the serpin gene superfamily. Serpins play roles in many processes including inflammation, blood clotting, and cancer metastasis. Members of this family have highly conserved secondary structures with a reactive center loop that interacts with the protease active site to inhibit protease activity. This gene encodes a plasma serine protease that functions as a thrombin and chymotrypsin inhibitor. The protein is activated by heparin, dermatan sulfate, and glycosaminoglycans. Allelic variations in this gene are associated with heparin cofactor II deficiency. [provided by RefSeq, Jul 2015]

PI4KA (HGNC:8983): (phosphatidylinositol 4-kinase alpha) This gene encodes a phosphatidylinositol (PI) 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. The protein encoded by this gene is a type III enzyme that is not inhibited by adenosine. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2018]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005047351).
• BP6: Variant 22-20779572-G-A is Benign according to our data. Variant chr22-20779572-G-A is described in ClinVar as [Benign]. Clinvar id is 781609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00738 (1124/152358) while in subpopulation AFR AF= 0.026 (1082/41584). AF 95% confidence interval is 0.0247. There are 10 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPIND1	NM_000185.4	c.260G>A	p.Ser87Asn	missense_variant	2/5	ENST00000215727.10
PI4KA	NM_058004.4	c.2328+13621C>T		intron_variant		ENST00000255882.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPIND1	ENST00000215727.10	c.260G>A	p.Ser87Asn	missense_variant	2/5	1	NM_000185.4	P1
PI4KA	ENST00000255882.11	c.2328+13621C>T		intron_variant		1	NM_058004.4	P1

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1124 AN: 152240 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00186 AC: 466 AN: 251070 Hom.: 6 AF XY: 0.00146 AC XY: 198 AN XY: 135696

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000719 AC: 1051 AN: 1461854 Hom.: 11 Cov.: 31 AF XY: 0.000587 AC XY: 427 AN XY: 727228

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00738 AC: 1124 AN: 152358 Hom.: 10 Cov.: 32 AF XY: 0.00709 AC XY: 528 AN XY: 74514

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00861

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SERPIND1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	15
Dann	Uncertain	0.97
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.55	D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.040	B;B
Vest4		0.14
MVP		0.89
MPC		0.12
ClinPred		0.023	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.24

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: rs34324685; hg19: chr22-21133860;