chr1-19814722-G-T

Variant names:

• chr1-19814722-G-T
• rs535476759
• NM_019062.2:c.380C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019062.2(RNF186):​c.380C>A​(p.Ala127Asp) 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. 14/22 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. A127V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF186 NM_019062.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.381
• Publications: 0 publications found

Genes affected

RNF186 (HGNC:25978): (ring finger protein 186) Enables ubiquitin-protein transferase activity. Involved in several processes, including intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein ubiquitination. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF186-AS1 (HGNC:41127): (RNF186 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14282808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF186	NM_019062.2	c.380C>A	p.Ala127Asp	missense_variant	Exon 1 of 1	ENST00000375121.4	NP_061935.1
RNF186-AS1	NR_186008.1	n.145+169G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF186	ENST00000375121.4	c.380C>A	p.Ala127Asp	missense_variant	Exon 1 of 1	6	NM_019062.2	ENSP00000364263.2
RNF186-AS1	ENST00000454736.2	n.200+169G>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.38
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.12	T
Sift4G	Uncertain	0.015	D
Polyphen		0.94	P
Vest4		0.25
MutPred		0.30		Gain of disorder (P = 0.0513);
MVP		0.56
MPC		0.68
ClinPred		0.39	T
GERP RS		2.0
Varity_R		0.15
gMVP		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs535476759; hg19: chr1-20141215;