22-20779530-G-A

Position:

• chr22-20779530-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000185.4(SERPIND1):​c.218G>A​(p.Gly73Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SERPIND1 NM_000185.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80

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]

PI4KA (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13099459).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPIND1	NM_000185.4	c.218G>A	p.Gly73Glu	missense_variant	2/5	ENST00000215727.10	NP_000176.2
PI4KA	NM_058004.4	c.2328+13663C>T		intron_variant		ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPIND1	ENST00000215727.10	c.218G>A	p.Gly73Glu	missense_variant	2/5	1	NM_000185.4	ENSP00000215727.5
PI4KA	ENST00000255882.11	c.2328+13663C>T		intron_variant		1	NM_058004.4	ENSP00000255882.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.026
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.99	L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.24
Sift	Benign	0.16	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.018	B;B
Vest4		0.26
MutPred		0.40		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.89
MPC		0.17
ClinPred		0.68	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1933582345; hg19: chr22-21133818; COSMIC: COSV104551280;