7-5064579-T-C

Position:

• chr7-5064579-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000396912.2(RBAK):​c.1123T>C​(p.Cys375Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBAK ENST00000396912.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53

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-RBAKDN (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBAK	NM_021163.4	c.1123T>C	p.Cys375Arg	missense_variant	5/5	ENST00000396912.2	NP_066986.1
RBAK-RBAKDN	NM_001204513.3	c.238+6800T>C		intron_variant			NP_001191442.1
RBAK	NM_001204456.2	c.1123T>C	p.Cys375Arg	missense_variant	6/6		NP_001191385.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBAK	ENST00000396912.2	c.1123T>C	p.Cys375Arg	missense_variant	5/5	1	NM_021163.4	ENSP00000380120	P1
RBAK	ENST00000353796.7	c.1123T>C	p.Cys375Arg	missense_variant	6/6	2		ENSP00000275423	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.1123T>C (p.C375R) alteration is located in exon 5 (coding exon 4) of the RBAK gene. This alteration results from a T to C substitution at nucleotide position 1123, causing the cysteine (C) at amino acid position 375 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.51	.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.3	H;H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-12	D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.61		Loss of catalytic residue at P374 (P = 0.0109);Loss of catalytic residue at P374 (P = 0.0109);
MVP		0.87
MPC		0.55
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-5104210;