chr16-574424-C-T

Variant names:

• chr16-574424-C-T
• rs111753944
• NM_004204.5:c.350C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004204.5(PIGQ):​c.350C>T​(p.Ala117Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,610,296 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0071 (43 hom.)
• Consequence: PIGQ NM_004204.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.986
• Publications: 3 publications found

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]

PIGQ Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 77

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000282907 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066652894).
• BP6: Variant 16-574424-C-T is Benign according to our data. Variant chr16-574424-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 456046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00488 (743/152322) while in subpopulation NFE AF = 0.00853 (580/68008). AF 95% confidence interval is 0.00795. There are 3 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004204.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGQ	NM_004204.5	MANE Select	c.350C>T	p.Ala117Val	missense	Exon 2 of 11	NP_004195.2
	PIGQ	NM_148920.4		c.350C>T	p.Ala117Val	missense	Exon 2 of 10	NP_683721.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGQ	ENST00000321878.10	TSL:1 MANE Select	c.350C>T	p.Ala117Val	missense	Exon 2 of 11	ENSP00000326674.6
	PIGQ	ENST00000026218.9	TSL:1	c.350C>T	p.Ala117Val	missense	Exon 2 of 10	ENSP00000026218.5
	PIGQ	ENST00000470411.2	TSL:1	c.350C>T	p.Ala117Val	missense	Exon 2 of 3	ENSP00000439650.1

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 743 AN: 152204 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00853

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00409 AC: 979 AN: 239530 AF XY: 0.00421

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.000719

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00750

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00707 AC: 10312 AN: 1457974 Hom.: 43 Cov.: 39 AF XY: 0.00684 AC XY: 4961 AN XY: 725108

African (AFR) AF: 0.00114 AC: 38 AN: 33454

American (AMR) AF: 0.00182 AC: 81 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.000807 AC: 21 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.000361 AC: 31 AN: 85784

European-Finnish (FIN) AF: 0.00360 AC: 186 AN: 51700

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00867 AC: 9634 AN: 1110950

Other (OTH) AF: 0.00531 AC: 320 AN: 60236

GnomAD4 genome AF: 0.00488 AC: 743 AN: 152322 Hom.: 3 Cov.: 34 AF XY: 0.00427 AC XY: 318 AN XY: 74470

African (AFR) AF: 0.00161 AC: 67 AN: 41576

American (AMR) AF: 0.00294 AC: 45 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00853 AC: 580 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00662 Hom.: 1

Bravo AF: 0.00491

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00722 AC: 62

ExAC AF: 0.00380 AC: 460

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 77 (1)
-	-	1	Epilepsy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	PIGQ-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.24
DANN	Benign	0.92
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.99
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.025
Sift	Benign	0.29	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.31
MPC		0.13
ClinPred		0.0029	T
GERP RS		0.030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.17
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs111753944; hg19: chr16-624424;