2-196847951-A-T

Position:

• chr2-196847951-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024989.4(PGAP1):​c.1948T>A​(p.Leu650Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,422,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L650F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PGAP1 NM_024989.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38860208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4	c.1948T>A	p.Leu650Met	missense_variant	21/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9	c.1948T>A	p.Leu650Met	missense_variant	21/27	1	NM_024989.4	P1
PGAP1	ENST00000423035.5	c.*1879T>A		3_prime_UTR_variant, NMD_transcript_variant	22/28	1
PGAP1	ENST00000409475.5	c.*75T>A		3_prime_UTR_variant	20/20	2
PGAP1	ENST00000470179.5	n.1412T>A		non_coding_transcript_exon_variant	17/22	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1422462 Hom.: 0 Cov.: 28 AF XY: 0.00000424 AC XY: 3 AN XY: 707518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000457

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2020

The c.1948T>A (p.L650M) alteration is located in exon 21 (coding exon 21) of the PGAP1 gene. This alteration results from a T to A substitution at nucleotide position 1948, causing the leucine (L) at amino acid position 650 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.083
Sift	Benign	0.036	D
Sift4G	Benign	0.063	T
Polyphen		0.99	D
Vest4		0.47
MutPred		0.34		Loss of helix (P = 0.0558);
MVP		0.46
MPC		0.66
ClinPred		0.87	D
GERP RS		4.2
Varity_R		0.16
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs1488181217; hg19: chr2-197712675;