rs1457240197

Variant names:

• chr2-196916556-C-G
• rs1457240197
• NM_024989.4:c.339G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-196916556-C-G
• chr2-196916556-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024989.4(PGAP1):​c.339G>C​(p.Glu113Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PGAP1 NM_024989.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.350
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.339G>C	p.Glu113Asp	missense	Exon 3 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.-184G>C		5_prime_UTR	Exon 4 of 28	NP_001308028.1	Q75T13-2
	PGAP1	NM_001321100.2		c.-773G>C		5_prime_UTR	Exon 3 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.339G>C	p.Glu113Asp	missense	Exon 3 of 27	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*270G>C		non_coding_transcript_exon	Exon 4 of 28	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000485830.1	TSL:1	n.483G>C		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460390 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726440

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111374

Other (OTH) AF: 0.0000497 AC: 3 AN: 60340

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal recessive 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.35
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.068	T
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.44		Loss of helix (P = 0.0626)
MVP		0.45
MPC		0.72
ClinPred		0.81	D
GERP RS		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.69
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1457240197; hg19: chr2-197781280;