Genetic Variant RLF:p.Ala8Asp (chr1-40161422-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_012421.4(RLF):c.23C>A(p.Ala8Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000452 in 1,549,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

RLF
NM_012421.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

1 publications found

Variant links:

Genes affected

RLF (HGNC:10025): (RLF zinc finger) Predicted to enable DNA binding activity and DNA-binding transcription activator activity, RNA polymerase II-specific. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to act upstream of or within histone H3-K4 monomethylation and regulation of DNA methylation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RLF links:

ENSG00000303499 (HGNC:):

ENSG00000303499 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2808648).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012421.4. 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
	RLF	NM_012421.4	MANE Select	c.23C>A	p.Ala8Asp	missense	Exon 1 of 8	NP_036553.2	Q13129

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLF	ENST00000372771.5	TSL:1 MANE Select	c.23C>A	p.Ala8Asp	missense	Exon 1 of 8	ENSP00000361857.4	Q13129
	ENSG00000303499	ENST00000795129.1		n.-165G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

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

GnomAD4 exome

AF:

0.00000429

AC:

AN:

1396986

Hom.:

Cov.:

AF XY:

0.00000722

AC XY:

AN XY:

692740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29178

American (AMR)

AF:

0.00

AC:

AN:

30032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22920

East Asian (EAS)

AF:

0.00

AC:

AN:

36096

South Asian (SAS)

AF:

0.00

AC:

AN:

78914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5344

European-Non Finnish (NFE)

AF:

0.00000553

AC:

AN:

1085568

Other (OTH)

AF:

0.00

AC:

AN:

57376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0016

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.089

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.39

M_CAP

Benign

0.035

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

1.1

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.18

REVEL

Benign

0.087

Sift

Uncertain

0.013

Sift4G

Uncertain

0.024

Polyphen

0.74

Vest4

0.60

MutPred

0.18

Gain of loop (P = 0.0079)

MVP

0.20

MPC

0.60

ClinPred

0.54

GERP RS

3.4

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.1

Varity_R

0.16

gMVP

0.45

Mutation Taster

=74/26

polymorphism

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over