rs138525017

Variant names:

• chr2-196897152-A-G
• rs138525017
• NM_024989.4:c.906T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024989.4(PGAP1):​c.906T>C​(p.Leu302Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,578,116 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (22 hom.)
• Consequence: PGAP1 NM_024989.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.850
• Publications: 2 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=-0.56).
• BP6: Variant 2-196897152-A-G is Benign according to our data. Variant chr2-196897152-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0027 (412/152328) while in subpopulation NFE AF = 0.00479 (326/68012). AF 95% confidence interval is 0.00437. There are 1 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR gene

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.906T>C	p.Leu302Leu	synonymous	Exon 7 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.384T>C	p.Leu128Leu	synonymous	Exon 8 of 28	NP_001308028.1	Q75T13-2
	PGAP1	NM_001321100.2		c.-206T>C		5_prime_UTR	Exon 7 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.906T>C	p.Leu302Leu	synonymous	Exon 7 of 27	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*837T>C		non_coding_transcript_exon	Exon 8 of 28	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000485830.1	TSL:1	n.1050T>C		non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00220 AC: 513 AN: 233676 AF XY: 0.00219

Gnomad AFR exome AF: 0.000899

Gnomad AMR exome AF: 0.000824

Gnomad ASJ exome AF: 0.00266

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000655

Gnomad NFE exome AF: 0.00377

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00492 AC: 7011 AN: 1425788 Hom.: 22 Cov.: 26 AF XY: 0.00467 AC XY: 3317 AN XY: 709536

African (AFR) AF: 0.000775 AC: 25 AN: 32246

American (AMR) AF: 0.000704 AC: 29 AN: 41192

Ashkenazi Jewish (ASJ) AF: 0.00271 AC: 69 AN: 25452

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38962

South Asian (SAS) AF: 0.000987 AC: 80 AN: 81018

European-Finnish (FIN) AF: 0.00104 AC: 55 AN: 52982

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5702

European-Non Finnish (NFE) AF: 0.00591 AC: 6436 AN: 1089022

Other (OTH) AF: 0.00530 AC: 314 AN: 59212

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00260 AC XY: 194 AN XY: 74490

African (AFR) AF: 0.00103 AC: 43 AN: 41586

American (AMR) AF: 0.00111 AC: 17 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

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

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00479 AC: 326 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00375 Hom.: 2

Bravo AF: 0.00279

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.74
PhyloP100		0.85
Mutation Taster		=100/0	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: rs138525017; hg19: chr2-197761876; COSMIC: COSV100698403;