Genetic Variant RBAK-RBAKDN:p.Arg101Leu (chr7-5072364-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001204513.3(RBAK-RBAKDN):c.241G>T(p.Ala81Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000046 in 1,521,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

RBAK-RBAKDN
NM_001204513.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.740

Publications

0 publications found

Variant links:

Genes affected

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:

RBAKDN (HGNC:33770): (RBAK downstream neighbor)

RBAKDN links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051249444).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204513.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBAK-RBAKDN	NM_001204513.3		c.241G>T	p.Ala81Ser	missense splice_region	Exon 5 of 6	NP_001191442.1	A0A0A6YYG8
	RBAKDN	NR_015343.2		n.144G>T		splice_region non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBAK-RBAKDN	ENST00000407184.5	TSL:2	c.302G>T	p.Arg101Leu	missense splice_region	Exon 7 of 8	ENSP00000385560.1	I3L0D1
RBAKDN	ENST00000498308.2	TSL:1	c.-16G>T		splice_region	Exon 2 of 3	ENSP00000520911.1	A0ABB0MVN3
RBAKDN	ENST00000498308.2	TSL:1	c.-16G>T		5_prime_UTR	Exon 2 of 3	ENSP00000520911.1	A0ABB0MVN3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000244

AC:

AN:

122980

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000223

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000438

AC:

AN:

1369560

Hom.:

Cov.:

AF XY:

0.00000445

AC XY:

AN XY:

673952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29890

American (AMR)

AF:

0.00

AC:

AN:

31426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23718

East Asian (EAS)

AF:

0.0000583

AC:

AN:

34308

South Asian (SAS)

AF:

0.00

AC:

AN:

76130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4374

European-Non Finnish (NFE)

AF:

0.00000281

AC:

AN:

1066262

Other (OTH)

AF:

0.0000177

AC:

AN:

56614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.3

(source)

DANN

Benign

0.97

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.15

M_CAP

Benign

0.0076

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

PhyloP100

0.74

PROVEAN

Benign

-0.43

REVEL

Benign

0.043

Sift

Benign

0.83

Sift4G

Benign

0.82

Vest4

0.091

MutPred

0.28

Gain of glycosylation at A81 (P = 0.0041)

MVP

0.093

MPC

0.21

ClinPred

0.026

GERP RS

2.2

gMVP

0.038

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Computational scores

Splicing

Publications

Other links and lift over