chr5-64214329-C-G

Position:

• chr5-64214329-C-G

Variant summary

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

The NM_001113561.2(RNF180):​c.1003C>G​(p.Leu335Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF180 NM_001113561.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.211

Genes affected

RNF180 (HGNC:27752): (ring finger protein 180) Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Predicted to be involved in norepinephrine metabolic process; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; and serotonin metabolic process. Predicted to act upstream of or within several processes, including adult behavior; positive regulation of protein ubiquitination; and protein polyubiquitination. Predicted to be located in nuclear envelope. Predicted to be integral component of membrane. Predicted to be intrinsic component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.101023585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF180	NM_001113561.2	c.1003C>G	p.Leu335Val	missense_variant	4/8	ENST00000389100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF180	ENST00000389100.9	c.1003C>G	p.Leu335Val	missense_variant	4/8	1	NM_001113561.2	P1
RNF180	ENST00000296615.10	c.1003C>G	p.Leu335Val	missense_variant	4/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

May 14, 2024

The c.1003C>G (p.L335V) alteration is located in exon 4 (coding exon 3) of the RNF180 gene. This alteration results from a C to G substitution at nucleotide position 1003, causing the leucine (L) at amino acid position 335 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.0054	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.045
Sift	Benign	0.19	T;T
Sift4G	Benign	0.88	T;T
Polyphen		0.64	P;B
Vest4		0.25
MutPred		0.15		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP		0.66
MPC		0.14
ClinPred		0.11	T
GERP RS		2.8
Varity_R		0.061
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-63510156;