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GeneBe

7-5064183-A-T

Variant summary

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

The NM_021163.4(RBAK):c.727A>T(p.Ile243Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RBAK
NM_021163.4 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62
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]

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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=0.045125276).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RBAKNM_021163.4 linkuse as main transcriptc.727A>T p.Ile243Leu missense_variant 5/5 ENST00000396912.2
RBAK-RBAKDNNM_001204513.3 linkuse as main transcriptc.238+6404A>T intron_variant
RBAKNM_001204456.2 linkuse as main transcriptc.727A>T p.Ile243Leu missense_variant 6/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RBAKENST00000396912.2 linkuse as main transcriptc.727A>T p.Ile243Leu missense_variant 5/51 NM_021163.4 P1Q9NYW8-1
RBAKENST00000353796.7 linkuse as main transcriptc.727A>T p.Ile243Leu missense_variant 6/62 P1Q9NYW8-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000265
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250382
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135446
show subpopulations
Gnomad AFR exome
AF:
0.000249
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461626
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
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:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.000265
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000642
ExAC
AF:
0.0000247
AC:
3

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 submitterclinical testingAmbry GeneticsOct 10, 2023The c.727A>T (p.I243L) alteration is located in exon 5 (coding exon 4) of the RBAK gene. This alteration results from a A to T substitution at nucleotide position 727, causing the isoleucine (I) at amino acid position 243 to be replaced by a leucine (L). 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
0.089
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.59
Cadd
Benign
13
Dann
Benign
0.72
DEOGEN2
Benign
0.021
T;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.0040
N
M_CAP
Benign
0.0013
T
MetaRNN
Benign
0.045
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.29
N;N
REVEL
Benign
0.043
Sift
Benign
1.0
T;T
Sift4G
Benign
0.65
T;T
Polyphen
0.0
B;B
Vest4
0.13
MutPred
0.31
Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP
0.072
MPC
0.071
ClinPred
0.013
T
GERP RS
1.1
Varity_R
0.095
gMVP
0.056

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.

Other links and lift over

dbSNP: rs200370611; hg19: chr7-5103814; API