rs6643

Positions:

• chr2-85597128-T-A
• chr2-85597128-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016494.4(RNF181):​c.352T>A​(p.Tyr118Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. Y118H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF181 NM_016494.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14928815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF181	NM_016494.4	c.352T>A	p.Tyr118Asn	missense_variant	4/5	ENST00000306368.9	NP_057578.1
RNF181	XM_005264359.5	c.393T>A	p.Ala131=	synonymous_variant	3/4		XP_005264416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF181	ENST00000306368.9	c.352T>A	p.Tyr118Asn	missense_variant	4/5	1	NM_016494.4	ENSP00000306906	P1
RNF181	ENST00000441634.5	c.352T>A	p.Tyr118Asn	missense_variant	4/4	2		ENSP00000412025
RNF181	ENST00000456023.1	c.342T>A	p.Ala114=	synonymous_variant	3/4	3		ENSP00000415246
RNF181	ENST00000443647.5	c.*80T>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	2		ENSP00000391326

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.096
Sift	Benign	0.047	D;T
Sift4G	Uncertain	0.020	D;D
Polyphen		0.0070	.;B
Vest4		0.15
MutPred		0.24		Gain of disorder (P = 0.0168);Gain of disorder (P = 0.0168);
MVP		0.56
MPC		0.46
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.30
gMVP		0.67

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: rs6643; hg19: chr2-85824251;