22-20779800-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000185.4(SERPIND1):c.488G>C(p.Gly163Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPIND1 NM_000185.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.29

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17204854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPIND1	NM_000185.4	c.488G>C	p.Gly163Ala	missense_variant	2/5	ENST00000215727.10
PI4KA	NM_058004.4	c.2328+13393C>G		intron_variant		ENST00000255882.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPIND1	ENST00000215727.10	c.488G>C	p.Gly163Ala	missense_variant	2/5	1	NM_000185.4	P1
PI4KA	ENST00000255882.11	c.2328+13393C>G		intron_variant		1	NM_058004.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Heparin cofactor II deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

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	0.075
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	13
Dann	Benign	0.69
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.99	N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.6	N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.016	B;B
Vest4		0.091
MutPred		0.72		Loss of disorder (P = 0.1219);Loss of disorder (P = 0.1219);
MVP		0.74
MPC		0.14
ClinPred		0.15	T
GERP RS		3.4
Varity_R		0.37
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-21134088;