chr22-20779543-C-T

Position:

• chr22-20779543-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000185.4(SERPIND1):​c.231C>T​(p.Asp77Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,613,928 control chromosomes in the GnomAD database, including 1,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (196 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (1442 hom.)
• Consequence: SERPIND1 NM_000185.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts 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]

PI4KA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 22-20779543-C-T is Benign according to our data. Variant chr22-20779543-C-T is described in ClinVar as [Benign]. Clinvar id is 1268540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPIND1	NM_000185.4	c.231C>T	p.Asp77Asp	synonymous_variant	2/5	ENST00000215727.10	NP_000176.2
PI4KA	NM_058004.4	c.2328+13650G>A		intron_variant		ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPIND1	ENST00000215727.10	c.231C>T	p.Asp77Asp	synonymous_variant	2/5	1	NM_000185.4	ENSP00000215727.5
PI4KA	ENST00000255882.11	c.2328+13650G>A		intron_variant		1	NM_058004.4	ENSP00000255882.6

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2410 AN: 152198 Hom.: 185 Cov.: 32

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0388 AC: 9735 AN: 251058 Hom.: 1188 AF XY: 0.0296 AC XY: 4015 AN XY: 135704

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0665

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.00910 AC: 13301 AN: 1461612 Hom.: 1442 Cov.: 31 AF XY: 0.00780 AC XY: 5673 AN XY: 727076

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0565

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0160 AC: 2437 AN: 152316 Hom.: 196 Cov.: 32 AF XY: 0.0170 AC XY: 1263 AN XY: 74486

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0638

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00182 Hom.: 43

Bravo AF: 0.0274

EpiCase AF: 0.000164

EpiControl AF: 0.000533

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.37
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs5903; hg19: chr22-21133831; COSMIC: COSV99300036;