1-26794649-C-T

Variant names:

• chr1-26794649-C-T
• rs34512715
• NM_017837.4:c.615C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017837.4(PIGV):​c.615C>T​(p.Asn205Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,208 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (24 hom.)
• Consequence: PIGV NM_017837.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.54
• Publications: 5 publications found

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]

PIGV Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-26794649-C-T is Benign according to our data. Variant chr1-26794649-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00927 (1412/152316) while in subpopulation AFR AF = 0.0319 (1325/41568). AF 95% confidence interval is 0.0304. There are 13 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017837.4. 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
	PIGV	NM_017837.4	MANE Select	c.615C>T	p.Asn205Asn	synonymous	Exon 3 of 4	NP_060307.2
	PIGV	NM_001202554.2		c.615C>T	p.Asn205Asn	synonymous	Exon 3 of 4	NP_001189483.1	Q9NUD9
	PIGV	NM_001374478.1		c.615C>T	p.Asn205Asn	synonymous	Exon 3 of 4	NP_001361407.1	Q9NUD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGV	ENST00000674202.1	MANE Select	c.615C>T	p.Asn205Asn	synonymous	Exon 3 of 4	ENSP00000501479.1	Q9NUD9
	PIGV	ENST00000078527.9	TSL:1	c.615C>T	p.Asn205Asn	synonymous	Exon 3 of 4	ENSP00000078527.4	Q9NUD9
	PIGV	ENST00000686325.1		c.615C>T	p.Asn205Asn	synonymous	Exon 3 of 4	ENSP00000509836.1	A0A8I5KVW7

Frequencies

GnomAD3 genomes AF: 0.00924 AC: 1406 AN: 152198 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00243 AC: 612 AN: 251442 AF XY: 0.00180

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000883 AC: 1291 AN: 1461892 Hom.: 24 Cov.: 34 AF XY: 0.000760 AC XY: 553 AN XY: 727246

African (AFR) AF: 0.0285 AC: 953 AN: 33480

American (AMR) AF: 0.00253 AC: 113 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000102 AC: 113 AN: 1112010

Other (OTH) AF: 0.00172 AC: 104 AN: 60396

GnomAD4 genome AF: 0.00927 AC: 1412 AN: 152316 Hom.: 13 Cov.: 32 AF XY: 0.00934 AC XY: 696 AN XY: 74490

African (AFR) AF: 0.0319 AC: 1325 AN: 41568

American (AMR) AF: 0.00392 AC: 60 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00475 Hom.: 5

Bravo AF: 0.0101

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hyperphosphatasia with intellectual disability syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.61
PhyloP100		-3.5
Mutation Taster		=98/2	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: rs34512715; hg19: chr1-27121140;