NM_178841.4:c.526G>C

Variant names:

• chr16-88698985-C-G
• rs558365512
• NM_178841.4:c.526G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_178841.4(RNF166):​c.526G>C​(p.Asp176His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D176N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RNF166 NM_178841.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73
• Publications: 0 publications found

Genes affected

RNF166 (HGNC:28856): (ring finger protein 166) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein polyubiquitination and ubiquitin-dependent protein catabolic process. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF166	NM_178841.4	c.526G>C	p.Asp176His	missense_variant	Exon 4 of 6	ENST00000312838.9	NP_849163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF166	ENST00000312838.9	c.526G>C	p.Asp176His	missense_variant	Exon 4 of 6	1	NM_178841.4	ENSP00000326095.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445198 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717524

African (AFR) AF: 0.00 AC: 0 AN: 33288

American (AMR) AF: 0.00 AC: 0 AN: 42506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 39176

South Asian (SAS) AF: 0.00 AC: 0 AN: 83800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104378

Other (OTH) AF: 0.00 AC: 0 AN: 59684

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-1.0	T
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.93
MutPred		0.33		Gain of disorder (P = 0.1418);.;.;.;.;
MVP		0.40
MPC		0.95
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.70

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: rs558365512; hg19: chr16-88765393;