rs5907

chr22-20779935-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000185.4(SERPIND1):c.623G>A(p.Arg208His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,202 control chromosomes in the GnomAD database, including 4 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. R208C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: SERPIND1 NM_000185.4 missense
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050468773).
• BS2: High AC in GnomAd at 236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPIND1	NM_000185.4	c.623G>A	p.Arg208His	missense_variant	2/5	ENST00000215727.10
PI4KA	NM_058004.4	c.2328+13258C>T		intron_variant		ENST00000255882.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPIND1	ENST00000215727.10	c.623G>A	p.Arg208His	missense_variant	2/5	1	NM_000185.4	P1
PI4KA	ENST00000255882.11	c.2328+13258C>T		intron_variant		1	NM_058004.4	P1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00138 AC: 346 AN: 251386 Hom.: 0 AF XY: 0.00138 AC XY: 187 AN XY: 135842

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00177 AC: 2593 AN: 1461890 Hom.: 3 Cov.: 31 AF XY: 0.00170 AC XY: 1236 AN XY: 727244

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.00211

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74484

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heparin cofactor II deficiency Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 25, 1989	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.029	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		0.98	D;D
Vest4		0.85
MVP		0.96
MPC		0.64
ClinPred		0.18	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.79

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: rs5907; hg19: chr22-21134223; COSMIC: COSV104551232;