7-5064183-A-G

Variant names:

• chr7-5064183-A-G
• rs200370611
• NM_021163.4:c.727A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021163.4(RBAK):​c.727A>G​(p.Ile243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,626 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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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: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]

ACMG classification

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=0.06720236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBAK	NM_021163.4	c.727A>G	p.Ile243Val	missense_variant	Exon 5 of 5	ENST00000396912.2	NP_066986.1
RBAK	NM_001204456.2	c.727A>G	p.Ile243Val	missense_variant	Exon 6 of 6		NP_001191385.1
RBAK-RBAKDN	NM_001204513.3	c.238+6404A>G		intron_variant	Intron 4 of 5		NP_001191442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBAK	ENST00000396912.2	c.727A>G	p.Ile243Val	missense_variant	Exon 5 of 5	1	NM_021163.4	ENSP00000380120.1
RBAK-RBAKDN	ENST00000407184.5	c.299+428A>G		intron_variant	Intron 6 of 7	2		ENSP00000385560.1
RBAK	ENST00000353796.7	c.727A>G	p.Ile243Val	missense_variant	Exon 6 of 6	2		ENSP00000275423.4
RBAK-RBAKDN	ENST00000396904.2	c.238+6404A>G		intron_variant	Intron 4 of 5	4		ENSP00000380112.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.68
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.011	.;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.035
Sift	Benign	0.59	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0020	B;B
Vest4		0.11
MutPred		0.29		Gain of catalytic residue at I243 (P = 0.0575);Gain of catalytic residue at I243 (P = 0.0575);
MVP		0.085
MPC		0.065
ClinPred		0.036	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.033

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

Other links and lift over

dbSNP: rs200370611; hg19: chr7-5103814;