rs869025578

Variant names:

• chr2-196873007-A-T
• rs869025578
• NM_024989.4:c.1572T>A
• PGAP1 p.Tyr524*

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024989.4(PGAP1):​c.1572T>A​(p.Tyr524*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000121 in 825,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: PGAP1 NM_024989.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.24
• Publications: 3 publications found

Genes affected

PGAP1 (HGNC:25712): (post-GPI attachment to proteins inositol deacylase 1) The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment. [provided by RefSeq, Jul 2017]

PGAP1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 42

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive spastic paraplegia type 67

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-196873007-A-T is Pathogenic according to our data. Variant chr2-196873007-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 222977.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024989.4. 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
	PGAP1	NM_024989.4	MANE Select	c.1572T>A	p.Tyr524*	stop_gained	Exon 17 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.1050T>A	p.Tyr350*	stop_gained	Exon 18 of 28	NP_001308028.1	Q75T13-2
	PGAP1	NM_001321100.2		c.405T>A	p.Tyr135*	stop_gained	Exon 16 of 26	NP_001308029.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP1	ENST00000354764.9	TSL:1 MANE Select	c.1572T>A	p.Tyr524*	stop_gained	Exon 17 of 27	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*1503T>A		non_coding_transcript_exon	Exon 18 of 28	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000423035.5	TSL:1	n.*1503T>A		3_prime_UTR	Exon 18 of 28	ENSP00000415405.1	F8WD75

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000121 AC: 1 AN: 825936 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 433124

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

African (AFR) AF: 0.00 AC: 0 AN: 17374

American (AMR) AF: 0.00 AC: 0 AN: 25232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19750

East Asian (EAS) AF: 0.00 AC: 0 AN: 32116

South Asian (SAS) AF: 0.00 AC: 0 AN: 59594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.00000173 AC: 1 AN: 577556

Other (OTH) AF: 0.00 AC: 0 AN: 38180

⚠️ 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 Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, autosomal recessive 42 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		1.2
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs869025578;

hg19: chr2-197737731;