11-3808299-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1 BP4_Strong BP6_Moderate BS1 BS2

The ENST00000300730.10(PGAP2):c.145T>C(p.Trp49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000741 in 1,551,456 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: PGAP2 ENST00000300730.10 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.66

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 Benign. Variant got -12 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045338273).
• BP6: Variant 11-3808299-T-C is Benign according to our data. Variant chr11-3808299-T-C is described in ClinVar as [Benign]. Clinvar id is 2641519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00394 (600/152196) while in subpopulation AFR AF= 0.0137 (567/41536). AF 95% confidence interval is 0.0127. There are 3 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP2	NM_001256236.1	c.145T>C	p.Trp49Arg	missense_variant	2/8
PGAP2	NM_001283038.1	c.145T>C	p.Trp49Arg	missense_variant	2/7
PGAP2	NM_001145438.2	c.145T>C	p.Trp49Arg	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP2	ENST00000300730.10	c.145T>C	p.Trp49Arg	missense_variant	2/7	1
PGAP2	ENST00000396993.8	c.-320T>C		5_prime_UTR_variant	2/6	1
PGAP2	ENST00000465237.6	n.81T>C		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152078 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000799 AC: 125 AN: 156390 Hom.: 1 AF XY: 0.000543 AC XY: 45 AN XY: 82934

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000486

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.000392 AC: 549 AN: 1399260 Hom.: 5 Cov.: 31 AF XY: 0.000317 AC XY: 219 AN XY: 690126

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.000644

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000213

Gnomad4 OTH exome AF: 0.000741

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152196 Hom.: 3 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74400

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00144 Hom.: 1

Bravo AF: 0.00434

ESP6500AA AF: 0.0152 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00114 AC: 28

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

PGAP2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.54	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D
Polyphen		0.99	D;.
Vest4		0.46
MutPred		0.38		Gain of disorder (P = 0.0036);Gain of disorder (P = 0.0036);
MVP		0.49
ClinPred		0.095	T
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs183093939; hg19: chr11-3829529;