Genetic Variant NM_012421.4:c.779C>G (chr1-40202583-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012421.4(RLF):c.779C>G(p.Ser260Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,546,532 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 51 hom. )

Consequence

RLF
NM_012421.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.99

Publications

9 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045910478).

BP6

Variant 1-40202583-C-G is Benign according to our data. Variant chr1-40202583-C-G is described in ClinVar as Benign. ClinVar VariationId is 771304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00347 (529/152246) while in subpopulation EAS AF = 0.0301 (156/5184). AF 95% confidence interval is 0.0262. There are 11 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 529 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.779C>G	p.Ser260Cys	missense	Exon 5 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.779C>G	p.Ser260Cys	missense	Exon 5 of 8	ENSP00000361857.4	Q13129

Frequencies

GnomAD3 genomes

AF:

0.00348

AC:

529

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0175

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.0300

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00646

AC:

1249

AN:

193200

AF XY:

0.00526

show subpopulations

Gnomad AFR exome

AF:

0.000614

Gnomad AMR exome

AF:

0.0453

Gnomad ASJ exome

AF:

0.000125

Gnomad EAS exome

AF:

0.0270

Gnomad FIN exome

AF:

0.000630

Gnomad NFE exome

AF:

0.000889

Gnomad OTH exome

AF:

0.00322

GnomAD4 exome

AF:

0.00280

AC:

3907

AN:

1394286

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

1837

AN XY:

692746

show subpopulations

African (AFR)

AF:

0.000243

AC:

AN:

28828

American (AMR)

AF:

0.0368

AC:

963

AN:

26174

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

24132

East Asian (EAS)

AF:

0.0404

AC:

1468

AN:

36328

South Asian (SAS)

AF:

0.00127

AC:

AN:

72574

European-Finnish (FIN)

AF:

0.00111

AC:

AN:

52928

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.00108

AC:

1179

AN:

1090136

Other (OTH)

AF:

0.00228

AC:

131

AN:

57576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.00347

AC:

529

AN:

152246

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41528

American (AMR)

AF:

0.0175

AC:

268

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.0301

AC:

156

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000926

AC:

AN:

68030

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00229

Hom.:

Bravo

AF:

0.00563

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00773

AC:

939

Asia WGS

AF:

0.0140

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

PhyloP100

3.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.9

REVEL

Benign

0.17

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.022

Polyphen

1.0

Vest4

0.72

MVP

0.36

MPC

0.76

ClinPred

0.013

GERP RS

5.0

Varity_R

0.20

gMVP

0.27

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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