11-3808296-A-G

Variant names:

• chr11-3808296-A-G
• rs1487813766
• ENST00000300730.10:c.142A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_001346398.2(PGAP2):​c.-28-2A>G variant causes a splice acceptor, intron 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. 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 NM_001346398.2 splice_acceptor, intron
• 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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023529412 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of -4, new splice context is: attttgtgttctttcaacAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP2	NM_001256236.1	c.142A>G	p.Arg48Gly	missense_variant, splice_region_variant	Exon 2 of 8		NP_001243165.1
PGAP2	NM_001283038.1	c.142A>G	p.Arg48Gly	missense_variant, splice_region_variant	Exon 2 of 7		NP_001269967.1
PGAP2	NM_001145438.2	c.142A>G	p.Arg48Gly	missense_variant, splice_region_variant	Exon 2 of 7		NP_001138910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP2	ENST00000300730.10	c.142A>G	p.Arg48Gly	missense_variant, splice_region_variant	Exon 2 of 7	1		ENSP00000300730.6
PGAP2	ENST00000396993.8	c.-323A>G		splice_region_variant	Exon 2 of 6	1		ENSP00000380190.6
PGAP2	ENST00000396993	c.-323A>G		5_prime_UTR_variant	Exon 2 of 6	1		ENSP00000380190.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 156406 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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 AC: 10 AN: 31596

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35704

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25182

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35738

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 79232

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 49158

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1078938

Gnomad4 Remaining exome AF: 0.000103 AC: 6 AN: 57998

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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
Mutation Taster		=83/17	polymorphism

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;