20-56474712-T-G

Position:

• chr20-56474712-T-G

Variant summary

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

The NM_016407.5(RTF2):​c.199T>G​(p.Leu67Val) 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 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: -0.349

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, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTF2	NM_016407.5	c.199T>G	p.Leu67Val	missense_variant	3/9	ENST00000357348.10	NP_057491.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTF2	ENST00000357348.10	c.199T>G	p.Leu67Val	missense_variant	3/9	1	NM_016407.5	ENSP00000349906.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Oct 01, 2024

The c.199T>G (p.L67V) alteration is located in exon 3 (coding exon 3) of the RTFDC1 gene. This alteration results from a T to G substitution at nucleotide position 199, causing the leucine (L) at amino acid position 67 to be replaced by a valine (V). 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	0.59
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;.;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.32	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	.;.;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.76
MutPred		0.96		Gain of methylation at K99 (P = 0.0627);.;.;Gain of methylation at K99 (P = 0.0627);
MVP		0.58
MPC		0.91
ClinPred		0.98	D
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.73

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: chr20-55049768;