NM_178841.4:c.472C>T

Variant names:

• chr16-88699039-G-A
• rs151028878
• NM_178841.4:c.472C>T

Variant summary

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

The NM_178841.4(RNF166):​c.472C>T​(p.Arg158Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,610,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: RNF166 NM_178841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178841.4. 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
	RNF166	NM_178841.4	MANE Select	c.472C>T	p.Arg158Cys	missense	Exon 4 of 6	NP_849163.1	Q96A37-1
	RNF166	NM_001171815.2		c.229C>T	p.Arg77Cys	missense	Exon 3 of 5	NP_001165286.1	Q96A37-3
	RNF166	NM_001171816.2		c.145C>T	p.Arg49Cys	missense	Exon 4 of 6	NP_001165287.1	Q96A37-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF166	ENST00000312838.9	TSL:1 MANE Select	c.472C>T	p.Arg158Cys	missense	Exon 4 of 6	ENSP00000326095.4	Q96A37-1
	RNF166	ENST00000956472.1		c.472C>T	p.Arg158Cys	missense	Exon 4 of 6	ENSP00000626531.1
	RNF166	ENST00000878562.1		c.457C>T	p.Arg153Cys	missense	Exon 4 of 6	ENSP00000548621.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000204 AC: 5 AN: 244640 AF XY: 0.0000301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000521 AC: 76 AN: 1458550 Hom.: 0 Cov.: 32 AF XY: 0.0000552 AC XY: 40 AN XY: 725242

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1110982

Other (OTH) AF: 0.0000332 AC: 2 AN: 60256

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000248 AC: 3

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	0.27
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.1	T
PhyloP100		2.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.36
MPC		1.0
ClinPred		0.95	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.69
Mutation Taster		=42/58	disease causing

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: rs151028878; hg19: chr16-88765447; COSMIC: COSV100455553; COSMIC: COSV100455553;