rs1312754435

Variant names:

• chr12-116750118-C-T
• rs1312754435
• NM_001382266.1:c.361C>T

Variant summary

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

The NM_001382266.1(RNFT2):​c.361C>T​(p.His121Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000319 in 1,565,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNFT2 NM_001382266.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• Publications: 0 publications found

Genes affected

RNFT2 (HGNC:25905): (ring finger protein, transmembrane 2) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in positive regulation of ERAD pathway and protein ubiquitination. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.1625191).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382266.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNFT2	NM_001382266.1	MANE Select	c.361C>T	p.His121Tyr	missense	Exon 4 of 11	NP_001369195.1	Q96EX2-1
	RNFT2	NM_001109903.2		c.361C>T	p.His121Tyr	missense	Exon 4 of 12	NP_001103373.1	Q96EX2-1
	RNFT2	NM_032814.4		c.361C>T	p.His121Tyr	missense	Exon 4 of 11	NP_116203.2	Q96EX2-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNFT2	ENST00000257575.9	TSL:5 MANE Select	c.361C>T	p.His121Tyr	missense	Exon 4 of 11	ENSP00000257575.4	Q96EX2-1
	RNFT2	ENST00000392549.7	TSL:5	c.361C>T	p.His121Tyr	missense	Exon 4 of 12	ENSP00000376332.2	Q96EX2-1
	RNFT2	ENST00000407967.7	TSL:5	c.361C>T	p.His121Tyr	missense	Exon 4 of 11	ENSP00000385669.3	Q96EX2-5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

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

GnomAD2 exomes AF: 0.00000552 AC: 1 AN: 181200 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000683

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1413740 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 700298

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32648

American (AMR) AF: 0.00 AC: 0 AN: 39706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.0000528 AC: 2 AN: 37874

South Asian (SAS) AF: 0.00 AC: 0 AN: 81322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094232

Other (OTH) AF: 0.00 AC: 0 AN: 58794

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.094
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		4.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.096
Sift	Benign	0.67	T
Sift4G	Uncertain	0.035	D
Polyphen		0.17	B
Vest4		0.35
MutPred		0.17		Gain of phosphorylation at H121 (P = 0.0535)
MVP		0.043
MPC		0.31
ClinPred		0.23	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.64
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs1312754435; hg19: chr12-117187923;