22-20779779-T-C

Position:

• chr22-20779779-T-C

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.467T>C​(p.Val156Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,614,220 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (34 hom.)
• Consequence: SERPIND1 NM_000185.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.56

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013924748).
• BP6: Variant 22-20779779-T-C is Benign according to our data. Variant chr22-20779779-T-C is described in ClinVar as [Benign]. Clinvar id is 731703.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 = 0.0106 (1612/152326) while in subpopulation AFR AF= 0.0354 (1473/41570). AF 95% confidence interval is 0.0339. There are 19 homozygotes in gnomad4. There are 796 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1612 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPIND1	NM_000185.4	c.467T>C	p.Val156Ala	missense_variant	2/5	ENST00000215727.10	NP_000176.2
PI4KA	NM_058004.4	c.2328+13414A>G		intron_variant		ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPIND1	ENST00000215727.10	c.467T>C	p.Val156Ala	missense_variant	2/5	1	NM_000185.4	ENSP00000215727.5
PI4KA	ENST00000255882.11	c.2328+13414A>G		intron_variant		1	NM_058004.4	ENSP00000255882.6

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1611 AN: 152208 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00320 AC: 803 AN: 251258 Hom.: 10 AF XY: 0.00251 AC XY: 341 AN XY: 135774

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000722

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00154 AC: 2255 AN: 1461894 Hom.: 34 Cov.: 31 AF XY: 0.00145 AC XY: 1056 AN XY: 727248

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000488

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.0106 AC: 1612 AN: 152326 Hom.: 19 Cov.: 32 AF XY: 0.0107 AC XY: 796 AN XY: 74478

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00258 Hom.: 10

Bravo AF: 0.0120

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00364 AC: 442

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000948

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	Labcorp Genetics (formerly Invitae), Labcorp	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	.;T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.43
Sift	Benign	0.15	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.71	P;P
Vest4		0.14
MVP		0.87
MPC		0.48
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.73
gMVP		0.56

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: rs116401176; hg19: chr22-21134067;