11-3808296-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The ENST00000300730.10(PGAP2):c.142A>G(p.Arg48Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,399,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PGAP2 ENST00000300730.10 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.00

Genes affected

PGAP2 (HGNC:17893): (post-GPI attachment to proteins 2) The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a chain Post-GPI attachment to proteins factor 2 (size 253) in uniprot entity PGAP2_HUMAN there are 29 pathogenic changes around while only 8 benign (78%) in ENST00000300730.10
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08169812).
• BP6: Variant 11-3808296-A-G is Benign according to our data. Variant chr11-3808296-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2255516.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP2	NM_001346398.2	c.-28-2A>G		splice_acceptor_variant
PGAP2	NM_001346400.2	c.-28-2A>G		splice_acceptor_variant
PGAP2	NM_001256236.1	c.142A>G	p.Arg48Gly	missense_variant, splice_region_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP2	ENST00000300730.10	c.142A>G	p.Arg48Gly	missense_variant, splice_region_variant	2/7	1
PGAP2	ENST00000396993.8	c.-323A>G		splice_region_variant, 5_prime_UTR_variant	2/6	1
PGAP2	ENST00000465237.6	n.78A>G		splice_region_variant, non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000121 AC: 17 AN: 1399238 Hom.: 0 Cov.: 31 AF XY: 0.0000174 AC XY: 12 AN XY: 690114

Gnomad4 AFR exome AF: 0.000316

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: 0.00

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.142A>G (p.R48G) alteration is located in exon 2 (coding exon 2) of the PGAP2 gene. This alteration results from a A to G substitution at nucleotide position 142, causing the arginine (R) at amino acid position 48 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

PGAP2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.064
Sift	Benign	0.057	T;T
Polyphen		0.46	P;.
Vest4		0.058
MutPred		0.24		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		0.29
ClinPred		0.25	T

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1487813766; hg19: chr11-3829526;