chr11-3808299-T-C

Variant names:

• chr11-3808299-T-C
• rs183093939
• ENST00000300730.10:c.145T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001346397.2(PGAP2):​c.127T>C​(p.Trp43Arg) 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. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: PGAP2 NM_001346397.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.66
• Publications: 3 publications found

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]

PGAP2 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• 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 Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346397.2. 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
	PGAP2	NM_001346397.2		c.127T>C	p.Trp43Arg	missense	Exon 2 of 7	NP_001333326.1
	PGAP2	NM_001283040.1		c.145T>C	p.Trp49Arg	missense	Exon 2 of 5	NP_001269969.1	Q9UHJ9
	PGAP2	NM_001346398.2		c.-27T>C		splice_region	Exon 2 of 7	NP_001333327.1	Q9UHJ9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000300730.10	TSL:1	c.145T>C	p.Trp49Arg	missense	Exon 2 of 7	ENSP00000300730.6	Q9UHJ9-5
	PGAP2	ENST00000396993.8	TSL:1	c.-320T>C		5_prime_UTR	Exon 2 of 6	ENSP00000380190.6	A8MZF5
	PGAP2	ENST00000465237.6	TSL:1	n.81T>C		non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.000799 AC: 125 AN: 156390 AF XY: 0.000543

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 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

African (AFR) AF: 0.0143 AC: 453 AN: 31592

American (AMR) AF: 0.000644 AC: 23 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35740

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49162

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5694

European-Non Finnish (NFE) AF: 0.0000213 AC: 23 AN: 1078956

Other (OTH) AF: 0.000741 AC: 43 AN: 57998

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

African (AFR) AF: 0.0137 AC: 567 AN: 41536

American (AMR) AF: 0.00124 AC: 19 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68010

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00167 Hom.: 2

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
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
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Polyphen		0.99	D
Vest4		0.46
MutPred		0.38		Gain of disorder (P = 0.0036)
MVP		0.49
ClinPred		0.095	T
GERP RS		3.1
PromoterAI		0.060	Neutral
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs183093939; hg19: chr11-3829529;