22-20779543-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000185.4(SERPIND1):c.231C>A(p.Asp77Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 1,613,960 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D77N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (94 hom.)
• Consequence: SERPIND1 NM_000185.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.11

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028539598).
• BP6: Variant 22-20779543-C-A is Benign according to our data. Variant chr22-20779543-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 788340.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS2: High AC in GnomAd at 1013 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPIND1	NM_000185.4	c.231C>A	p.Asp77Glu	missense_variant	2/5	ENST00000215727.10
PI4KA	NM_058004.4	c.2328+13650G>T		intron_variant		ENST00000255882.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPIND1	ENST00000215727.10	c.231C>A	p.Asp77Glu	missense_variant	2/5	1	NM_000185.4	P1
PI4KA	ENST00000255882.11	c.2328+13650G>T		intron_variant		1	NM_058004.4	P1

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1013 AN: 152200 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00678 AC: 1703 AN: 251058 Hom.: 16 AF XY: 0.00706 AC XY: 958 AN XY: 135704

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00974 AC: 14231 AN: 1461642 Hom.: 94 Cov.: 31 AF XY: 0.00952 AC XY: 6919 AN XY: 727080

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00447

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00292

Gnomad4 FIN exome AF: 0.00343

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00665 AC: 1013 AN: 152318 Hom.: 10 Cov.: 32 AF XY: 0.00605 AC XY: 451 AN XY: 74488

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.0112 Hom.: 43

Bravo AF: 0.00712

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00693 AC: 841

EpiCase AF: 0.00905

EpiControl AF: 0.00836

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PI4KA: BS1, BS2; SERPIND1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Heparin cofactor II deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.0030
Dann	Benign	0.88
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.29	N;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.54	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.13
MutPred		0.23		Gain of disorder (P = 0.2123);Gain of disorder (P = 0.2123);
MVP		0.36
MPC		0.11
ClinPred		0.0039	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.099

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5903; hg19: chr22-21133831;