16-568088-C-T

Variant names:

• chr16-568088-C-T
• NM_001301159.2:c.41C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001301159.2(NHLRC4):​c.41C>T​(p.Pro14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NHLRC4 NM_001301159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

Genes affected

NHLRC4 (HGNC:26700): (NHL repeat containing 4) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein K48-linked ubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297509 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.289519).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301159.2. 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
	NHLRC4	NM_001301159.2	MANE Select	c.41C>T	p.Pro14Leu	missense	Exon 2 of 2	NP_001288088.1	P0CG21
	NHLRC4	NM_176677.3		c.41C>T	p.Pro14Leu	missense	Exon 2 of 2	NP_788850.1	P0CG21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC4	ENST00000424439.3	TSL:3 MANE Select	c.41C>T	p.Pro14Leu	missense	Exon 2 of 2	ENSP00000410858.2	P0CG21
	NHLRC4	ENST00000540585.1	TSL:1	c.41C>T	p.Pro14Leu	missense	Exon 2 of 2	ENSP00000442223.1	P0CG21
	PIGQ	ENST00000409527.6	TSL:2	c.-10+525C>T		intron	N/A	ENSP00000386760.2	Q9BRB3-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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	Benign	0.16
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.28
Sift	Benign	0.044	D
Sift4G	Benign	0.67	T
Polyphen		0.68	P
Vest4		0.34
MutPred		0.43		Loss of disorder (P = 0.017)
MVP		0.56
MPC		0.039
ClinPred		0.92	D
GERP RS		3.5
Varity_R		0.11
gMVP		0.26

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

hg19: chr16-618088;