Genetic Variant NM_021163.4:c.290A>C (chr7-5063746-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_021163.4(RBAK):c.290A>C(p.Lys97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RBAK
NM_021163.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.699

Variant links:

Genes affected

RBAK (HGNC:17680): (RB associated KRAB zinc finger) This gene encodes a nuclear protein which interacts with the tumor suppressor retinoblastoma 1. The two interacting proteins are thought to act as a transcriptional repressor for promoters which are activated by the E2F1 transcription factor. This protein contains a Kruppel-associated box (KRAB), which is a transcriptional repressor motif. Read-through transcripts that include exons from the downstream gene LOC389458 are expressed from this locus. [provided by RefSeq, Mar 2011]

RBAK links:

RBAK-RBAKDN (HGNC:42971): (RBAK-RBAKDN readthrough) This locus represents naturally occurring read-through transcription between the neighboring RBAK (RB-associated KRAB zinc finger) and LOC389458 (hypothetical LOC389458) genes on chromosome 7. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product but its C-terminal region is distinct due to frameshifts relative to the downstream gene. [provided by RefSeq, Mar 2011]

RBAK-RBAKDN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity RBAK_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.079997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBAK	NM_021163.4 link	c.290A>C	p.Lys97Thr	missense_variant	Exon 5 of 5	ENST00000396912.2	NP_066986.1	Q9NYW8-1
RBAK	NM_001204456.2 link	c.290A>C	p.Lys97Thr	missense_variant	Exon 6 of 6		NP_001191385.1	Q9NYW8-1
RBAK-RBAKDN	NM_001204513.3 link	c.238+5967A>C		intron_variant	Intron 4 of 5		NP_001191442.1	A0A0A6YYG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBAK	ENST00000396912.2 link	c.290A>C	p.Lys97Thr	missense_variant	Exon 5 of 5	1	NM_021163.4	ENSP00000380120.1		Q9NYW8-1
RBAK-RBAKDN	ENST00000407184.5 link	c.290A>C	p.Lys97Thr	missense_variant	Exon 6 of 8	2		ENSP00000385560.1		I3L0D1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249950

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135094

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726600

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.4

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.36

T;.;T

M_CAP

Benign

0.0016

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.9

N;D;D

REVEL

Benign

0.039

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.55

T;T;T

Polyphen

0.037

.;B;B

Vest4

0.13

MutPred

0.33

Loss of ubiquitination at K97 (P = 0.0074);Loss of ubiquitination at K97 (P = 0.0074);Loss of ubiquitination at K97 (P = 0.0074);

MVP

0.043

MPC

0.10

ClinPred

0.10

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.075

gMVP

0.071

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over