chr16-372128-C-G

Variant names:

• chr16-372128-C-G
• NM_021259.3:c.2175G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021259.3(PGAP6):​c.2175G>C​(p.Trp725Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PGAP6 NM_021259.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01
• Publications: 0 publications found

Genes affected

PGAP6 (HGNC:17205): (post-GPI attachment to proteins 6) Predicted to enable phospholipase A2 activity. Located in extracellular exosome and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021259.3. 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
	PGAP6	NM_021259.3	MANE Select	c.2175G>C	p.Trp725Cys	missense	Exon 13 of 13	NP_067082.2	Q9HCN3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP6	ENST00000431232.7	TSL:1 MANE Select	c.2175G>C	p.Trp725Cys	missense	Exon 13 of 13	ENSP00000401338.2	Q9HCN3
	PGAP6	ENST00000946607.1		c.2364G>C	p.Trp788Cys	missense	Exon 13 of 13	ENSP00000616666.1
	PGAP6	ENST00000930879.1		c.2196G>C	p.Trp732Cys	missense	Exon 13 of 13	ENSP00000600938.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460630 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726626

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.73		Loss of helix (P = 0.2022)
MVP		0.74
MPC		0.35
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr16-422128;