Variant 1-40161412-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_012421.4(RLF):c.13A>G(p.Lys5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,543,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

RLF
NM_012421.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.07

Variant links:

Genes affected

RLF (HGNC:10025): (RLF zinc finger) Predicted to enable DNA binding activity and DNA-binding transcription activator activity, RNA polymerase II-specific. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to act upstream of or within histone H3-K4 monomethylation and regulation of DNA methylation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RLF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18521142).

BS2

High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLF	NM_012421.4 linkuse as main transcript	c.13A>G	p.Lys5Glu	missense_variant	1/8	ENST00000372771.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLF	ENST00000372771.5 linkuse as main transcript	c.13A>G	p.Lys5Glu	missense_variant	1/8	1	NM_012421.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000309

AC:

AN:

1391984

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

689846

show subpopulations

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:

0.0000378

Gnomad4 OTH exome

AF:

0.0000350

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.13A>G (p.K5E) alteration is located in exon 1 (coding exon 1) of the RLF gene. This alteration results from a A to G substitution at nucleotide position 13, causing the lysine (K) at amino acid position 5 to be replaced by a glutamic acid (E). 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

0.21

BayesDel_addAF

Benign

0.0082

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0016

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.48

M_CAP

Benign

0.023

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.90

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.050

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.096

Vest4

0.51

MVP

0.63

MPC

0.56

ClinPred

0.48

GERP RS

4.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.45

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over