rs5906

Variant names:

• chr22-20779597-C-T
• rs5906
• NM_000185.4:c.285C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-20779597-C-T
• chr22-20779597-C-A
• chr22-20779597-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000185.4(SERPIND1):​c.285C>T​(p.Ile95Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,614,172 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (70 hom.)
• Consequence: SERPIND1 NM_000185.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.754
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 22-20779597-C-T is Benign according to our data. Variant chr22-20779597-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.754 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00586 (893/152358) while in subpopulation EAS AF = 0.0548 (284/5186). AF 95% confidence interval is 0.0495. There are 8 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 893 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.285C>T	p.Ile95Ile	synonymous	Exon 2 of 5	NP_000176.2	P05546-1
	PI4KA	NM_058004.4	MANE Select	c.2328+13596G>A		intron	N/A	NP_477352.3	P42356-1
	PI4KA	NM_001362863.2		c.2262+13596G>A		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.285C>T	p.Ile95Ile	synonymous	Exon 2 of 5	ENSP00000215727.5	P05546-1
	SERPIND1	ENST00000406799.1	TSL:1	c.285C>T	p.Ile95Ile	synonymous	Exon 1 of 4	ENSP00000384050.1	P05546-1
	PI4KA	ENST00000255882.11	TSL:1 MANE Select	c.2328+13596G>A		intron	N/A	ENSP00000255882.6	P42356-1

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 897 AN: 152240 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00741 AC: 1861 AN: 251062 AF XY: 0.00730

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0566

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00585 AC: 8551 AN: 1461814 Hom.: 70 Cov.: 31 AF XY: 0.00582 AC XY: 4229 AN XY: 727202

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00376 AC: 168 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.0476 AC: 1888 AN: 39696

South Asian (SAS) AF: 0.00182 AC: 157 AN: 86258

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53420

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.00520 AC: 5787 AN: 1111936

Other (OTH) AF: 0.00634 AC: 383 AN: 60396

GnomAD4 genome AF: 0.00586 AC: 893 AN: 152358 Hom.: 8 Cov.: 32 AF XY: 0.00564 AC XY: 420 AN XY: 74508

African (AFR) AF: 0.00221 AC: 92 AN: 41584

American (AMR) AF: 0.00758 AC: 116 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0548 AC: 284 AN: 5186

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00522 AC: 355 AN: 68036

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00499 Hom.: 5

Bravo AF: 0.00653

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	SERPIND1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.4
DANN	Benign	0.81
PhyloP100		0.75
PromoterAI		-0.0067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs5906; hg19: chr22-21133885; COSMIC: COSV53138801;