2-85595788-G-C

Position:

• chr2-85595788-G-C

Variant summary

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

The NM_016494.4(RNF181):​c.25G>C​(p.Asp9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNF181 NM_016494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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]

RNF181 (HGNC:):

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.25G>C	p.Asp9His	missense_variant	1/5	ENST00000306368.9	NP_057578.1
RNF181	XM_005264359.5	c.25G>C	p.Asp9His	missense_variant	1/4		XP_005264416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF181	ENST00000306368.9	c.25G>C	p.Asp9His	missense_variant	1/5	1	NM_016494.4	ENSP00000306906.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 27, 2024

The c.25G>C (p.D9H) alteration is located in exon 1 (coding exon 1) of the RNF181 gene. This alteration results from a G to C substitution at nucleotide position 25, causing the aspartic acid (D) at amino acid position 9 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.0	.;M;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N;N;D
REVEL	Uncertain	0.49
Sift	Benign	0.089	T;T;D
Sift4G	Benign	0.21	T;T;D
Polyphen		0.89	.;P;.
Vest4		0.46
MutPred		0.23		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.68
MPC		0.66
ClinPred		0.93	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.16
gMVP		0.64

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: rs375414610; hg19: chr2-85822911;