chr16-88698990-C-T

Variant names:

• chr16-88698990-C-T
• rs377640480
• NM_178841.4:c.521G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_178841.4(RNF166):​c.521G>A​(p.Arg174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 1,601,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R174C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: RNF166 NM_178841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062854856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF166	NM_178841.4	c.521G>A	p.Arg174His	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.521G>A	p.Arg174His	missense_variant	Exon 4 of 6	1	NM_178841.4	ENSP00000326095.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000113 AC: 26 AN: 230814 AF XY: 0.0000720

Gnomad AFR exome AF: 0.0000713

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000359 AC: 52 AN: 1449092 Hom.: 0 Cov.: 32 AF XY: 0.0000320 AC XY: 23 AN XY: 719754

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.000556 AC: 24 AN: 43132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39374

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84314

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51398

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5566

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1106304

Other (OTH) AF: 0.00 AC: 0 AN: 59830

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000122 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.521G>A (p.R174H) alteration is located in exon 4 (coding exon 4) of the RNF166 gene. This alteration results from a G to A substitution at nucleotide position 521, causing the arginine (R) at amino acid position 174 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.063	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		3.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.11	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;D;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.53
MVP		0.34
MPC		0.96
ClinPred		0.74	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.54
Mutation Taster		=68/32	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: rs377640480; hg19: chr16-88765398; COSMIC: COSV100455544; COSMIC: COSV100455544;