1-26787988-A-C

Position:

• chr1-26787988-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017837.4(PIGV):​c.-338A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 152,310 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (346 hom., cov: 32)
  • Exomes 𝑓: 0.091 (1 hom.)
• Consequence: PIGV NM_017837.4 5_prime_UTR
• Scores: Splicing: ADA: 0.00002453
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.643

Genes affected

PIGV (HGNC:26031): (phosphatidylinositol glycan anchor biosynthesis class V) This gene encodes a mannosyltransferase enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is a complex glycolipid that functions as a membrane anchor for many proteins and plays a role in multiple cellular processes including protein sorting and signal transduction. The encoded protein is localized to the endoplasmic reticulum and transfers the second mannose to the GPI backbone. Mutations in this gene are associated with hyperphosphatasia cognitive disability syndrome. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-26787988-A-C is Benign according to our data. Variant chr1-26787988-A-C is described in ClinVar as [Benign]. Clinvar id is 297110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGV	NM_017837.4	c.-338A>C		5_prime_UTR_variant	1/4	ENST00000674202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGV	ENST00000674202.1	c.-338A>C		5_prime_UTR_variant	1/4		NM_017837.4	P1

Frequencies

GnomAD3 genomes AF: 0.0583 AC: 8858 AN: 152040 Hom.: 346 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0130

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0857

Gnomad OTH AF: 0.0645

GnomAD4 exome AF: 0.0909 AC: 14 AN: 154 Hom.: 1 Cov.: 0 AF XY: 0.0859 AC XY: 11 AN XY: 128

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.0956

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0582 AC: 8852 AN: 152156 Hom.: 346 Cov.: 32 AF XY: 0.0560 AC XY: 4166 AN XY: 74398

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.0412

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.0130

Gnomad4 SAS AF: 0.0532

Gnomad4 FIN AF: 0.0750

Gnomad4 NFE AF: 0.0857

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0726 Hom.: 61

Bravo AF: 0.0530

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hyperphosphatasia with intellectual disability syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0020

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

Publications

LitVar

Other links and lift over

dbSNP: rs113400508; hg19: chr1-27114479;