chr20-56484131-G-A

Position:

• chr20-56484131-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016407.5(RTF2):​c.419G>A​(p.Cys140Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTF2	NM_016407.5	c.419G>A	p.Cys140Tyr	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.419G>A	p.Cys140Tyr	missense_variant	5/9	1	NM_016407.5	ENSP00000349906	P1
RTF2	ENST00000023939.8	c.509G>A	p.Cys170Tyr	missense_variant	6/10	2		ENSP00000023939
RTF2	ENST00000449062.1	c.509G>A	p.Cys170Tyr	missense_variant	6/9	5		ENSP00000400322
RTF2	ENST00000395881.7	c.419G>A	p.Cys140Tyr	missense_variant	5/8	2		ENSP00000379220

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Jan 22, 2024

The c.419G>A (p.C140Y) alteration is located in exon 5 (coding exon 5) of the RTFDC1 gene. This alteration results from a G to A substitution at nucleotide position 419, causing the cysteine (C) at amino acid position 140 to be replaced by a tyrosine (Y). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.038	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-11	.;.;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.98
MutPred		0.92		Gain of sheet (P = 0.1208);.;.;Gain of sheet (P = 0.1208);
MVP		0.93
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.86

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: chr20-55059187;