20-56484116-G-T

Position:

• chr20-56484116-G-T

Variant summary

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

The NM_016407.5(RTF2):​c.404G>T​(p.Cys135Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RTF2 NM_016407.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

RTF2 (HGNC:15890): (replication termination factor 2) Enables DNA binding activity. Involved in cellular response to hydroxyurea and regulation of DNA stability. Located in replication fork. [provided by Alliance of Genome Resources, Apr 2022]

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
RTF2	NM_016407.5	c.404G>T	p.Cys135Phe	missense_variant	5/9	ENST00000357348.10	NP_057491.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTF2	ENST00000357348.10	c.404G>T	p.Cys135Phe	missense_variant	5/9	1	NM_016407.5	ENSP00000349906	P1
RTF2	ENST00000023939.8	c.494G>T	p.Cys165Phe	missense_variant	6/10	2		ENSP00000023939
RTF2	ENST00000449062.1	c.494G>T	p.Cys165Phe	missense_variant	6/9	5		ENSP00000400322
RTF2	ENST00000395881.7	c.404G>T	p.Cys135Phe	missense_variant	5/8	2		ENSP00000379220

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727202

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 02, 2023

The c.404G>T (p.C135F) alteration is located in exon 5 (coding exon 5) of the RTFDC1 gene. This alteration results from a G to T substitution at nucleotide position 404, causing the cysteine (C) at amino acid position 135 to be replaced by a phenylalanine (F). 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	0.49
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.068	.;.;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.5	.;.;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.024	.;.;D;D
Sift4G	Uncertain	0.044	D;D;T;T
Polyphen		0.15	.;.;B;.
Vest4		0.89
MutPred		0.59		Loss of sheet (P = 0.1501);.;.;Loss of sheet (P = 0.1501);
MVP		0.54
MPC		0.43
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.74

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: chr20-55059172;