NM_000185.4:c.231C>A

Variant names:

• chr22-20779543-C-A
• rs5903
• NM_000185.4:c.231C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000185.4(SERPIND1):​c.231C>A​(p.Asp77Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 1,613,960 control chromosomes in the GnomAD database, including 104 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D77N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (94 hom.)
• Consequence: SERPIND1 NM_000185.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.11
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028539598).
• BP6: Variant 22-20779543-C-A is Benign according to our data. Variant chr22-20779543-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 788340.
• BS2: High AC in GnomAd4 at 1013 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000185.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPIND1	NM_000185.4	MANE Select	c.231C>A	p.Asp77Glu	missense	Exon 2 of 5	NP_000176.2	P05546-1
	PI4KA	NM_058004.4	MANE Select	c.2328+13650G>T		intron	N/A	NP_477352.3	P42356-1
	PI4KA	NM_001362863.2		c.2262+13650G>T		intron	N/A	NP_001349792.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPIND1	ENST00000215727.10	TSL:1 MANE Select	c.231C>A	p.Asp77Glu	missense	Exon 2 of 5	ENSP00000215727.5	P05546-1
	SERPIND1	ENST00000406799.1	TSL:1	c.231C>A	p.Asp77Glu	missense	Exon 1 of 4	ENSP00000384050.1	P05546-1
	PI4KA	ENST00000255882.11	TSL:1 MANE Select	c.2328+13650G>T		intron	N/A	ENSP00000255882.6	P42356-1

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1013 AN: 152200 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00678 AC: 1703 AN: 251058 AF XY: 0.00706

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00974 AC: 14231 AN: 1461642 Hom.: 94 Cov.: 31 AF XY: 0.00952 AC XY: 6919 AN XY: 727080

African (AFR) AF: 0.00143 AC: 48 AN: 33476

American (AMR) AF: 0.00447 AC: 200 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 269 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00292 AC: 252 AN: 86258

European-Finnish (FIN) AF: 0.00343 AC: 183 AN: 53418

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0115 AC: 12835 AN: 1111814

Other (OTH) AF: 0.00689 AC: 416 AN: 60382

GnomAD4 genome AF: 0.00665 AC: 1013 AN: 152318 Hom.: 10 Cov.: 32 AF XY: 0.00605 AC XY: 451 AN XY: 74488

African (AFR) AF: 0.00209 AC: 87 AN: 41568

American (AMR) AF: 0.00386 AC: 59 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4824

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0108 AC: 732 AN: 68032

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.0122 Hom.: 86

Bravo AF: 0.00712

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00693 AC: 841

EpiCase AF: 0.00905

EpiControl AF: 0.00836

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Heparin cofactor II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.0030
DANN	Benign	0.88
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.29	N
PhyloP100		-2.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.23		Gain of disorder (P = 0.2123)
MVP		0.36
MPC		0.11
ClinPred		0.0039	T
GERP RS		-12
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.099
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5903; hg19: chr22-21133831;