chr22-20779779-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V156F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 34 hom. )

Consequence

SERPIND1
NM_000185.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.56

Variant links:

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]

SERPIND1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SERPIND1	NM_000185.4 link	c.467T>C	p.Val156Ala	missense_variant	Exon 2 of 5	ENST00000215727.10	NP_000176.2	P05546Q8IVC0
PI4KA	NM_058004.4 link	c.2328+13414A>G		intron_variant	Intron 19 of 54	ENST00000255882.11	NP_477352.3	P42356-1Q4LE69B4DYG5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPIND1	ENST00000215727.10 link	c.467T>C	p.Val156Ala	missense_variant	Exon 2 of 5	1	NM_000185.4	ENSP00000215727.5		P05546
PI4KA	ENST00000255882.11 link	c.2328+13414A>G		intron_variant	Intron 19 of 54	1	NM_058004.4	ENSP00000255882.6		P42356-1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1611

AN:

152208

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00251

AC XY:

341

AN XY:

135774

show subpopulations

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.:

Cov.:

AF XY:

0.00145

AC XY:

1056

AN XY:

727248

show subpopulations

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.:

Cov.:

AF XY:

0.0107

AC XY:

796

AN XY:

74478

show subpopulations

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.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0354

AC:

156

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00364

AC:

442

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;D

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

.;T

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.44

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over