Genetic Variant NM_001145664.2:c.1417G>T (chr2-101397553-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001145664.2(RFX8):c.1417G>T(p.Val473Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V473M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

RFX8
NM_001145664.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.839

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050341666).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145664.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFX8	NM_001145664.2	MANE Select	c.1417G>T	p.Val473Leu	missense	Exon 12 of 12	NP_001139136.2	Q6ZV50-3
RFX8	NM_001367508.1		c.904G>T	p.Val302Leu	missense	Exon 13 of 13	NP_001354437.1
RFX8	NM_001367509.1		c.904G>T	p.Val302Leu	missense	Exon 14 of 14	NP_001354438.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFX8	ENST00000428343.6	TSL:2 MANE Select	c.1417G>T	p.Val473Leu	missense	Exon 12 of 12	ENSP00000401536.1	Q6ZV50-3
RFX8	ENST00000646893.2		c.1756G>T	p.Val586Leu	missense	Exon 15 of 15	ENSP00000494249.2	Q6ZV50-1
RFX8	ENST00000646446.1		c.1630G>T	p.Val544Leu	missense	Exon 15 of 15	ENSP00000494216.1	A0A2R8Y560

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1385348

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31200

American (AMR)

AF:

0.00

AC:

AN:

34310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24874

East Asian (EAS)

AF:

0.00

AC:

AN:

35554

South Asian (SAS)

AF:

0.00

AC:

AN:

76874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070214

Other (OTH)

AF:

0.00

AC:

AN:

57530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.4

(source)

DANN

Benign

0.84

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.38

M_CAP

Benign

0.0053

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.95

PhyloP100

-0.84

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.41

REVEL

Benign

0.041

Sift

Benign

0.051

Sift4G

Benign

0.098

Polyphen

0.012

Vest4

0.039

MVP

0.030

MPC

0.00050

ClinPred

0.054

GERP RS

-3.9

gMVP

0.016

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over