NM_024989.4:c.534T>G

Variant names:

• chr2-196912997-A-C
• rs35444896
• NM_024989.4:c.534T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024989.4(PGAP1):​c.534T>G​(p.Leu178Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,613,862 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (117 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (107 hom.)
• Consequence: PGAP1 NM_024989.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.654
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-196912997-A-C is Benign according to our data. Variant chr2-196912997-A-C is described in ClinVar as Benign. ClinVar VariationId is 474993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.654 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

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.534T>G	p.Leu178Leu	synonymous	Exon 4 of 27	NP_079265.2
	PGAP1	NM_001321100.2		c.-578T>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 26	NP_001308029.1
	PGAP1	NM_001321099.2		c.12T>G	p.Leu4Leu	synonymous	Exon 5 of 28	NP_001308028.1	Q75T13-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP1	ENST00000354764.9	TSL:1 MANE Select	c.534T>G	p.Leu178Leu	synonymous	Exon 4 of 27	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*465T>G		non_coding_transcript_exon	Exon 5 of 28	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000485830.1	TSL:1	n.678T>G		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3273 AN: 152174 Hom.: 117 Cov.: 33

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00618 AC: 1552 AN: 251054 AF XY: 0.00448

Gnomad AFR exome AF: 0.0774

Gnomad AMR exome AF: 0.00528

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00268 AC: 3921 AN: 1461570 Hom.: 107 Cov.: 32 AF XY: 0.00238 AC XY: 1727 AN XY: 727094

African (AFR) AF: 0.0779 AC: 2607 AN: 33458

American (AMR) AF: 0.00629 AC: 281 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86230

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00729 AC: 42 AN: 5762

European-Non Finnish (NFE) AF: 0.000550 AC: 612 AN: 1111864

Other (OTH) AF: 0.00566 AC: 342 AN: 60374

GnomAD4 genome AF: 0.0216 AC: 3286 AN: 152292 Hom.: 117 Cov.: 33 AF XY: 0.0208 AC XY: 1548 AN XY: 74476

African (AFR) AF: 0.0738 AC: 3066 AN: 41522

American (AMR) AF: 0.0105 AC: 160 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68028

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.0119 Hom.: 49

Bravo AF: 0.0244

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Intellectual disability, autosomal recessive 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.6
DANN	Benign	0.77
PhyloP100		0.65
Mutation Taster		=94/6	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

Other links and lift over

dbSNP: rs35444896; hg19: chr2-197777721;