16-88697611-G-T

Variant names:

• chr16-88697611-G-T
• rs367841158
• NM_178841.4:c.671C>A

Variant summary

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

The NM_178841.4(RNF166):​c.671C>A​(p.Ala224Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,774 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A224G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNF166 NM_178841.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.44
• 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]

ENSG00000259813 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF166	NM_178841.4	c.671C>A	p.Ala224Asp	missense_variant	Exon 6 of 6	ENST00000312838.9	NP_849163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF166	ENST00000312838.9	c.671C>A	p.Ala224Asp	missense_variant	Exon 6 of 6	1	NM_178841.4	ENSP00000326095.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399774 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690600

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31656

American (AMR) AF: 0.00 AC: 0 AN: 36016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 35930

South Asian (SAS) AF: 0.00 AC: 0 AN: 79336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1079682

Other (OTH) AF: 0.00 AC: 0 AN: 58058

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.043	T;.;.;.
Eigen	Benign	0.093
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;.;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.60	T;T;T;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.92	P;.;.;.
Vest4		0.67
MutPred		0.46		Loss of helix (P = 0.0138);.;.;.;
MVP		0.15
MPC		0.35
ClinPred		0.71	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.89
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs367841158; hg19: chr16-88764019;