rs377584268

Positions:

• chr16-579136-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_004204.5(PIGQ):​c.1291G>A​(p.Val431Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,612,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.83

Genes affected

PIGQ (HGNC:14135): (phosphatidylinositol glycan anchor biosynthesis class Q) This gene is involved in the first step in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes a N-acetylglucosaminyl transferase component that is part of the complex that catalyzes transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14799988).
• BP6: Variant 16-579136-G-A is Benign according to our data. Variant chr16-579136-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456030.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGQ	NM_004204.5	c.1291G>A	p.Val431Ile	missense_variant	7/11	ENST00000321878.10
PIGQ	NM_148920.4	c.1291G>A	p.Val431Ile	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGQ	ENST00000321878.10	c.1291G>A	p.Val431Ile	missense_variant	7/11	1	NM_004204.5	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000224 AC: 56 AN: 250358 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000173 AC: 252 AN: 1460704 Hom.: 1 Cov.: 31 AF XY: 0.000173 AC XY: 126 AN XY: 726670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152292 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74446

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.1291G>A (p.V431I) alteration is located in exon 7 (coding exon 6) of the PIGQ gene. This alteration results from a G to A substitution at nucleotide position 1291, causing the valine (V) at amino acid position 431 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2022

- -

Epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	0.044
Eigen_PC	Benign	0.081
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.11	T;T;T;D
Polyphen		0.44	B;B;D;.
Vest4		0.47
MVP		0.28
MPC		0.16
ClinPred		0.082	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377584268; hg19: chr16-629136;