16-88698985-C-T

Variant names:

• chr16-88698985-C-T
• rs558365512
• NM_178841.4:c.526G>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.526G>A​(p.Asp176Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,597,530 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: RNF166 NM_178841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73
• Publications: 3 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=0.038824886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF166	NM_178841.4	c.526G>A	p.Asp176Asn	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>A	p.Asp176Asn	missense_variant	Exon 4 of 6	1	NM_178841.4	ENSP00000326095.4

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000325 AC: 73 AN: 224594 AF XY: 0.000271

Gnomad AFR exome AF: 0.000220

Gnomad AMR exome AF: 0.000345

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.0000591

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000902

Gnomad OTH exome AF: 0.000536

GnomAD4 exome AF: 0.000152 AC: 219 AN: 1445196 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 96 AN XY: 717522

African (AFR) AF: 0.0000901 AC: 3 AN: 33288

American (AMR) AF: 0.000423 AC: 18 AN: 42506

Ashkenazi Jewish (ASJ) AF: 0.00481 AC: 124 AN: 25776

East Asian (EAS) AF: 0.0000255 AC: 1 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: 5486

European-Non Finnish (NFE) AF: 0.0000462 AC: 51 AN: 1104378

Other (OTH) AF: 0.000369 AC: 22 AN: 59684

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74484

African (AFR) AF: 0.000144 AC: 6 AN: 41584

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.000208 AC: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.526G>A (p.D176N) 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 526, causing the aspartic acid (D) at amino acid position 176 to be replaced by an asparagine (N). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.039	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.4	N;D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.055	T;T;T;T;T
Sift4G	Benign	0.088	T;T;T;T;T
Polyphen		0.96	D;.;.;.;.
Vest4		0.84
MutPred		0.36		Loss of catalytic residue at D176 (P = 0.031);.;.;.;.;
MVP		0.36
MPC		0.58
ClinPred		0.088	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.55
Mutation Taster		=70/30	polymorphism

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; COSMIC: COSV57189474; COSMIC: COSV57189474;