17-59963174-T-C

Position:

• chr17-59963174-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016125.4(RNFT1):​c.167A>G​(p.Asp56Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNFT1 NM_016125.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.72

Genes affected

RNFT1 (HGNC:30206): (ring finger protein, transmembrane 1) Enables ubiquitin binding activity and ubiquitin protein ligase activity. Involved in positive regulation of ERAD pathway and protein autoubiquitination. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267318 (HGNC:):

TBC1D3P1-DHX40P1 (HGNC:42362): (TBC1D3P1-DHX40P1 readthrough, transcribed pseudogene) This locus represents naturally-occurring readthrough transcription that extends through two unprocessed pseudogenes, TBC1D3P1 (TBC1 domain family member 3 pseudogene 1) and DHX40P1 (DEAH-box helicase 40 pseudogene 1), to protein-coding RNFT1 (ring finger protein, transmembrane 1). The individual pseudogene loci are not curated as transcribed regions. The readthrough transcript likely does not encode a functional protein, since translation of the long open reading frames would render the transcript a candidate for nonsense-mediated decay (NMD). [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047038555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNFT1	NM_016125.4	c.167A>G	p.Asp56Gly	missense_variant	2/9	ENST00000305783.13	NP_057209.3
TBC1D3P1-DHX40P1	NR_002924.3	n.1317A>G		non_coding_transcript_exon_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNFT1	ENST00000305783.13	c.167A>G	p.Asp56Gly	missense_variant	2/9	1	NM_016125.4	ENSP00000304670.8
ENSG00000267318	ENST00000591035.1	c.150-3229T>C		intron_variant		3		ENSP00000468280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Dec 11, 2023

The c.167A>G (p.D56G) alteration is located in exon 2 (coding exon 2) of the RNFT1 gene. This alteration results from a A to G substitution at nucleotide position 167, causing the aspartic acid (D) at amino acid position 56 to be replaced by a glycine (G). 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	0.068
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.4
DANN	Benign	0.91
DEOGEN2	Benign	0.0076	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.039
Sift	Benign	0.33	T;.
Sift4G	Benign	0.11	T;T
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.095		Loss of stability (P = 0.0765);Loss of stability (P = 0.0765);
MVP		0.12
MPC		0.20
ClinPred		0.047	T
GERP RS		-5.4
Varity_R		0.087
gMVP		0.18

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: rs2045308249; hg19: chr17-58040535;