rs757747543

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS1

The ENST00000327155.10(RBBP8):c.1223_1228delTAAATA(p.Ile408_Asn409del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,612,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RBBP8
ENST00000327155.10 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.27

Publications

0 publications found

Variant links:

Genes affected

RBBP8 (HGNC:9891): (RB binding protein 8, endonuclease) The protein encoded by this gene is a ubiquitously expressed nuclear protein. It is found among several proteins that bind directly to retinoblastoma protein, which regulates cell proliferation. This protein complexes with transcriptional co-repressor CTBP. It is also associated with BRCA1 and is thought to modulate the functions of BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control. It is suggested that this gene may itself be a tumor suppressor acting in the same pathway as BRCA1. Three transcript variants encoding two different isoforms have been found for this gene. More transcript variants exist, but their full-length natures have not been determined. [provided by RefSeq, Jul 2008]

RBBP8 Gene-Disease associations (from GenCC):

Jawad syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
Seckel syndrome 2
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
Seckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RBBP8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000327155.10.

BP6

Variant 18-22993047-TTATAAA-T is Benign according to our data. Variant chr18-22993047-TTATAAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436511.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000026 (38/1460474) while in subpopulation MID AF = 0.00104 (6/5754). AF 95% confidence interval is 0.000454. There are 0 homozygotes in GnomAdExome4. There are 22 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000327155.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBBP8	NM_002894.3	MANE Select	c.1223_1228delTAAATA	p.Ile408_Asn409del	disruptive_inframe_deletion	Exon 11 of 19	NP_002885.1
RBBP8	NM_203291.2		c.1223_1228delTAAATA	p.Ile408_Asn409del	disruptive_inframe_deletion	Exon 11 of 19	NP_976036.1
RBBP8	NM_203292.2		c.1223_1228delTAAATA	p.Ile408_Asn409del	disruptive_inframe_deletion	Exon 11 of 18	NP_976037.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RBBP8	ENST00000327155.10	TSL:1 MANE Select	c.1223_1228delTAAATA	p.Ile408_Asn409del	disruptive_inframe_deletion	Exon 11 of 19	ENSP00000323050.5
RBBP8	ENST00000360790.9	TSL:1	c.1223_1228delTAAATA	p.Ile408_Asn409del	disruptive_inframe_deletion	Exon 11 of 19	ENSP00000354024.5
RBBP8	ENST00000399722.6	TSL:1	c.1223_1228delTAAATA	p.Ile408_Asn409del	disruptive_inframe_deletion	Exon 11 of 19	ENSP00000382628.2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000360

AC:

AN:

249764

AF XY:

0.0000590

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1460474

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

726596

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1110966

Other (OTH)

AF:

0.0000497

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Jawad syndrome;C1847572:Seckel syndrome 2 (1)

not provided (1)

not specified (1)

Seckel syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=102/98

polymorphism

(source)

Splicing

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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over