rs61751989

Variant names:

• chr18-62146032-A-T
• rs61751989
• NM_176787.5:c.806-7T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_176787.5(PIGN):​c.806-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,302,290 control chromosomes in the GnomAD database, including 36,857 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3711 hom., cov: 32)
  • Exomes 𝑓: 0.23 (33146 hom.)
• Consequence: PIGN NM_176787.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.704
• Publications: 9 publications found

Genes affected

PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

PIGN Gene-Disease associations (from GenCC):

• multiple congenital anomalies-hypotonia-seizures syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 18-62146032-A-T is Benign according to our data. Variant chr18-62146032-A-T is described in ClinVar as Benign. ClinVar VariationId is 403306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176787.5. 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
	PIGN	NM_176787.5	MANE Select	c.806-7T>A		splice_region intron	N/A	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.806-7T>A		splice_region intron	N/A	NP_001425825.1
	PIGN	NM_012327.6		c.806-7T>A		splice_region intron	N/A	NP_036459.1	O95427

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.806-7T>A		splice_region intron	N/A	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.806-7T>A		splice_region intron	N/A	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.806-7T>A		splice_region intron	N/A	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32267 AN: 151946 Hom.: 3710 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.221

GnomAD2 exomes AF: 0.196 AC: 40291 AN: 205274 AF XY: 0.197

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.00284

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.234 AC: 268913 AN: 1150226 Hom.: 33146 Cov.: 15 AF XY: 0.231 AC XY: 134461 AN XY: 582682

African (AFR) AF: 0.198 AC: 5077 AN: 25638

American (AMR) AF: 0.127 AC: 4169 AN: 32914

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 5437 AN: 21948

East Asian (EAS) AF: 0.00127 AC: 48 AN: 37750

South Asian (SAS) AF: 0.116 AC: 8179 AN: 70482

European-Finnish (FIN) AF: 0.237 AC: 12305 AN: 51816

Middle Eastern (MID) AF: 0.255 AC: 1264 AN: 4956

European-Non Finnish (NFE) AF: 0.259 AC: 221499 AN: 855452

Other (OTH) AF: 0.222 AC: 10935 AN: 49270

GnomAD4 genome AF: 0.212 AC: 32289 AN: 152064 Hom.: 3711 Cov.: 32 AF XY: 0.207 AC XY: 15398 AN XY: 74310

African (AFR) AF: 0.193 AC: 7986 AN: 41480

American (AMR) AF: 0.170 AC: 2590 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 869 AN: 3470

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5190

South Asian (SAS) AF: 0.109 AC: 527 AN: 4830

European-Finnish (FIN) AF: 0.246 AC: 2593 AN: 10544

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.249 AC: 16915 AN: 67964

Other (OTH) AF: 0.223 AC: 470 AN: 2108

Alfa AF: 0.238 Hom.: 1469

Bravo AF: 0.208

Asia WGS AF: 0.0870 AC: 306 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.1
DANN	Benign	0.57
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61751989;

hg19: chr18-59813265;