2-85595798-C-T

Position:

• chr2-85595798-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016494.4(RNF181):​c.35C>T​(p.Pro12Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF181 NM_016494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

Genes affected

RNF181 (HGNC:28037): (ring finger protein 181) RNF181 binds the integrin alpha-IIb (ITGA2B; MIM 607759)/beta-3 (ITGB3; MIM 173470) complex and has E3 ubiquitin ligase activity (Brophy et al., 2008 [PubMed 18331836]).[supplied by OMIM, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF181	NM_016494.4	c.35C>T	p.Pro12Leu	missense_variant	1/5	ENST00000306368.9	NP_057578.1
RNF181	XM_005264359.5	c.35C>T	p.Pro12Leu	missense_variant	1/4		XP_005264416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF181	ENST00000306368.9	c.35C>T	p.Pro12Leu	missense_variant	1/5	1	NM_016494.4	ENSP00000306906	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152166 Hom.: 0 Cov.: 32 FAILED QC

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.35C>T (p.P12L) alteration is located in exon 1 (coding exon 1) of the RNF181 gene. This alteration results from a C to T substitution at nucleotide position 35, causing the proline (P) at amino acid position 12 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.033
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.1	.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.14	T;T;T
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.015	.;B;.
Vest4		0.18
MutPred		0.26		Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);Loss of loop (P = 0.0128);
MVP		0.70
MPC		0.26
ClinPred		0.94	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.17
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs765575244; hg19: chr2-85822921;