2-151437328-T-G

Position:

• chr2-151437328-T-G

Variant summary

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

The NM_018151.5(RIF1):​c.1460T>G​(p.Val487Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,996 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: 0.0000014 (0 hom.)
• Consequence: RIF1 NM_018151.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

Genes affected

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RIF1 (HGNC:):

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
RIF1	NM_018151.5	c.1460T>G	p.Val487Gly	missense_variant	13/36	ENST00000444746.7	NP_060621.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIF1	ENST00000444746.7	c.1460T>G	p.Val487Gly	missense_variant	13/36	1	NM_018151.5	ENSP00000390181.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460996 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726860

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: 0.0000232

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

Feb 23, 2023

The c.1460T>G (p.V487G) alteration is located in exon 13 (coding exon 12) of the RIF1 gene. This alteration results from a T to G substitution at nucleotide position 1460, causing the valine (V) at amino acid position 487 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	0.25
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	.;.;.;T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.9	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.47
MutPred		0.41		Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);
MVP		0.22
MPC		0.27
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.45

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: chr2-152293842;