rs138671843

Variant names:

• chr18-62074825-GA-G
• rs138671843
• NM_176787.5:c.2577-5delT

Your query was ambiguous. Multiple possible variants found:

• chr18-62074825-GA-G
• chr18-62074825-GA-GAA
• chr18-62074825-GA-GAAA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_176787.5(PIGN):​c.2577-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,572,492 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: PIGN NM_176787.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0730
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 18-62074825-GA-G is Benign according to our data. Variant chr18-62074825-GA-G is described in ClinVar as Benign. ClinVar VariationId is 1610886.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2577-5delT		splice_region intron	N/A	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.2577-5delT		splice_region intron	N/A	NP_001425825.1
	PIGN	NM_012327.6		c.2577-5delT		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.2577-5delT		splice_region intron	N/A	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.2577-5delT		splice_region intron	N/A	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.*545-5delT		splice_region intron	N/A	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000263 AC: 55 AN: 208964 AF XY: 0.000283

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.000226

Gnomad EAS exome AF: 0.000404

Gnomad FIN exome AF: 0.000200

Gnomad NFE exome AF: 0.000243

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 165 AN: 1422300 Hom.: 1 Cov.: 26 AF XY: 0.000109 AC XY: 77 AN XY: 707718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000617 AC: 2 AN: 32438

American (AMR) AF: 0.0000930 AC: 4 AN: 43032

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25396

East Asian (EAS) AF: 0.00111 AC: 43 AN: 38640

South Asian (SAS) AF: 0.000133 AC: 11 AN: 82604

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52496

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5628

European-Non Finnish (NFE) AF: 0.0000877 AC: 95 AN: 1083290

Other (OTH) AF: 0.0000681 AC: 4 AN: 58776

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73236

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000244 AC: 1 AN: 40984

American (AMR) AF: 0.00 AC: 0 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67450

Other (OTH) AF: 0.00 AC: 0 AN: 2076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.073

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.050		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: rs138671843;

hg19: chr18-59742058;

COSMIC: COSV62947908;