Variant 2-101405996-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145664.2(RFX8):c.875T>G(p.Leu292Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000878 in 1,549,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

RFX8
NM_001145664.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90

Variant links:

Genes affected

RFX8 (HGNC:37253): (regulatory factor X8) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

RFX8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04599136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX8	NM_001145664.2 linkuse as main transcript	c.875T>G	p.Leu292Arg	missense_variant	10/12	ENST00000428343.6	NP_001139136.2	Q6ZV50-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX8	ENST00000428343.6 linkuse as main transcript	c.875T>G	p.Leu292Arg	missense_variant	10/12	2	NM_001145664.2	ENSP00000401536.1		Q6ZV50-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000591

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000173

AC:

AN:

155914

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

82462

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000331

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.0000851

AC:

119

AN:

1397770

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

689220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000169

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000343

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000677

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.000112

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000120

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Nov 05, 2021

The c.875T>G (p.L292R) alteration is located in exon 10 (coding exon 9) of the RFX8 gene. This alteration results from a T to G substitution at nucleotide position 875, causing the leucine (L) at amino acid position 292 to be replaced by an arginine (R). 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

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.10

Eigen_PC

Benign

0.0052

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.046

T;T;T

MetaSVM

Benign

-0.81

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.3

.;.;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

.;.;D

Sift4G

Uncertain

0.0020

.;.;D

Polyphen

0.55

.;.;P

Vest4

0.64

MVP

0.15

MPC

.;.;3.71968781554E-4

ClinPred

0.15

GERP RS

5.2

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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