rs34231046

Variant names:

• chr18-62045940-A-C
• rs34231046
• NM_176787.5:c.2712T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001438896.1(PIGN):​c.2829T>G​(p.Phe943Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,384 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (145 hom.)
• Consequence: PIGN NM_001438896.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.753
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia
• 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 (MetaRNN=0.005876571).
• BP6: Variant 18-62045940-A-C is Benign according to our data. Variant chr18-62045940-A-C is described in ClinVar as Benign. ClinVar VariationId is 472226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00831 (1266/152310) while in subpopulation NFE AF = 0.0144 (980/68020). AF 95% confidence interval is 0.0137. There are 6 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438896.1. 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.2712T>G	p.Phe904Leu	missense	Exon 31 of 31	NP_789744.1
	PIGN	NM_001438896.1		c.2829T>G	p.Phe943Leu	missense	Exon 32 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.2712T>G	p.Phe904Leu	missense	Exon 30 of 30	NP_036459.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.2712T>G	p.Phe904Leu	missense	Exon 31 of 31	ENSP00000492233.1
	PIGN	ENST00000400334.7	TSL:1	c.2712T>G	p.Phe904Leu	missense	Exon 30 of 30	ENSP00000383188.2
	PIGN	ENST00000638424.1	TSL:5	n.*680T>G		non_coding_transcript_exon	Exon 29 of 29	ENSP00000491963.1

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1266 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00937 AC: 2327 AN: 248306 AF XY: 0.00976

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00433

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00553

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.00861

GnomAD4 exome AF: 0.0122 AC: 17805 AN: 1461074 Hom.: 145 Cov.: 30 AF XY: 0.0120 AC XY: 8710 AN XY: 726762

African (AFR) AF: 0.00185 AC: 62 AN: 33472

American (AMR) AF: 0.00459 AC: 205 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00479 AC: 125 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00791 AC: 681 AN: 86110

European-Finnish (FIN) AF: 0.00562 AC: 300 AN: 53388

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.0142 AC: 15818 AN: 1111514

Other (OTH) AF: 0.00935 AC: 564 AN: 60350

GnomAD4 genome AF: 0.00831 AC: 1266 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74476

African (AFR) AF: 0.00255 AC: 106 AN: 41570

American (AMR) AF: 0.00373 AC: 57 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4826

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0144 AC: 980 AN: 68020

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0112 Hom.: 31

Bravo AF: 0.00822

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00222 AC: 9

ESP6500EA AF: 0.0127 AC: 107

ExAC AF: 0.00995 AC: 1203

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Inborn genetic diseases (1)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.75
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.093
Sift	Benign	0.097	T
Sift4G	Benign	0.28	T
Polyphen		0.024	B
Vest4		0.27
MutPred		0.15		Loss of MoRF binding (P = 0.4134)
MVP		0.31
MPC		0.026
ClinPred		0.036	T
GERP RS		0.22
Varity_R		0.21
gMVP		0.25
Mutation Taster		=88/12	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: rs34231046; hg19: chr18-59713173;