NM_001301159.2:c.230G>C

Variant names:

• chr16-568277-G-C
• rs376666202
• NM_001301159.2:c.230G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001301159.2(NHLRC4):​c.230G>C​(p.Arg77Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NHLRC4 NM_001301159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.499
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09415454).

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.230G>C	p.Arg77Pro	missense	Exon 2 of 2	NP_001288088.1	P0CG21
	NHLRC4	NM_176677.3		c.230G>C	p.Arg77Pro	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.230G>C	p.Arg77Pro	missense	Exon 2 of 2	ENSP00000410858.2	P0CG21
	NHLRC4	ENST00000540585.1	TSL:1	c.230G>C	p.Arg77Pro	missense	Exon 2 of 2	ENSP00000442223.1	P0CG21
	PIGQ	ENST00000409527.6	TSL:2	c.-10+714G>C		intron	N/A	ENSP00000386760.2	Q9BRB3-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111618

Other (OTH) AF: 0.00 AC: 0 AN: 60316

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	0.13
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	1.8
DANN	Benign	0.77
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.93	L
PhyloP100		-0.50
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.023	D
Sift4G	Benign	0.27	T
Polyphen		0.0030	B
Vest4		0.10
MutPred		0.37		Gain of catalytic residue at P76 (P = 0.0126)
MVP		0.19
MPC		0.016
ClinPred		0.084	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.32
gMVP		0.60
Mutation Taster		=79/21	polymorphism

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: rs376666202; hg19: chr16-618277;