NM_014489.4:c.-30C>G

Variant names:

• chr11-3808632-C-G
• rs61896956
• NM_014489.4:c.-30C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014489.4(PGAP2):​c.-30C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,293,316 control chromosomes in the GnomAD database, including 9,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (850 hom., cov: 32)
  • Exomes 𝑓: 0.12 (8576 hom.)
• Consequence: PGAP2 NM_014489.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.768
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-3808632-C-G is Benign according to our data. Variant chr11-3808632-C-G is described in ClinVar as Benign. ClinVar VariationId is 1279122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014489.4. 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_014489.4	MANE Select	c.-30C>G		5_prime_UTR	Exon 1 of 7	NP_055304.1	Q9UHJ9-2
	PGAP2	NM_001256240.2		c.-30C>G		5_prime_UTR	Exon 1 of 6	NP_001243169.1	Q9UHJ9-1
	PGAP2	NM_001256239.2		c.-30C>G		5_prime_UTR	Exon 1 of 6	NP_001243168.1	A0A0S2Z568

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000278243.9	TSL:1 MANE Select	c.-30C>G		5_prime_UTR	Exon 1 of 7	ENSP00000278243.4	Q9UHJ9-2
	PGAP2	ENST00000300730.10	TSL:1	c.161+317C>G		intron	N/A	ENSP00000300730.6	Q9UHJ9-5
	PGAP2	ENST00000396993.8	TSL:1	c.-304+317C>G		intron	N/A	ENSP00000380190.6	A8MZF5

Frequencies

GnomAD3 genomes AF: 0.0904 AC: 13748 AN: 152122 Hom.: 851 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.116

GnomAD4 exome AF: 0.118 AC: 134696 AN: 1141076 Hom.: 8576 Cov.: 30 AF XY: 0.117 AC XY: 64153 AN XY: 549132

African (AFR) AF: 0.0190 AC: 431 AN: 22696

American (AMR) AF: 0.0987 AC: 1153 AN: 11686

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 1797 AN: 14038

East Asian (EAS) AF: 0.000571 AC: 13 AN: 22758

South Asian (SAS) AF: 0.0598 AC: 3163 AN: 52890

European-Finnish (FIN) AF: 0.0896 AC: 1815 AN: 20266

Middle Eastern (MID) AF: 0.148 AC: 438 AN: 2968

European-Non Finnish (NFE) AF: 0.128 AC: 121119 AN: 948710

Other (OTH) AF: 0.106 AC: 4767 AN: 45064

GnomAD4 genome AF: 0.0903 AC: 13744 AN: 152240 Hom.: 850 Cov.: 32 AF XY: 0.0887 AC XY: 6606 AN XY: 74438

African (AFR) AF: 0.0230 AC: 957 AN: 41564

American (AMR) AF: 0.112 AC: 1716 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3472

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5162

South Asian (SAS) AF: 0.0510 AC: 246 AN: 4828

European-Finnish (FIN) AF: 0.0923 AC: 979 AN: 10610

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.131 AC: 8928 AN: 67998

Other (OTH) AF: 0.114 AC: 240 AN: 2108

Alfa AF: 0.0473 Hom.: 47

Bravo AF: 0.0896

Asia WGS AF: 0.0270 AC: 94 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.38
PhyloP100		-0.77
PromoterAI		0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61896956; hg19: chr11-3829862;