rs10889205

chr1-40240054-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_012421.4(RLF):c.5352A>T(p.Glu1784Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,606 control chromosomes in the GnomAD database, including 32,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3274 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29507 hom.)
• Consequence: RLF NM_012421.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.30

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RLF
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015485883).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLF	NM_012421.4	c.5352A>T	p.Glu1784Asp	missense_variant	8/8	ENST00000372771.5
RLF	XM_047427055.1	c.4704A>T	p.Glu1568Asp	missense_variant	6/6
RLF	XM_047427057.1	c.4185A>T	p.Glu1395Asp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLF	ENST00000372771.5	c.5352A>T	p.Glu1784Asp	missense_variant	8/8	1	NM_012421.4	P1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30771 AN: 152066 Hom.: 3271 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.0681

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.201

GnomAD3 exomes AF: 0.176 AC: 44174 AN: 250630 Hom.: 4354 AF XY: 0.171 AC XY: 23209 AN XY: 135534

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.0498

Gnomad SAS exome AF: 0.0746

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.196 AC: 286255 AN: 1461422 Hom.: 29507 Cov.: 35 AF XY: 0.191 AC XY: 139085 AN XY: 727026

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.0742

Gnomad4 SAS exome AF: 0.0761

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.202 AC: 30775 AN: 152184 Hom.: 3274 Cov.: 32 AF XY: 0.200 AC XY: 14903 AN XY: 74400

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.0571

Gnomad4 SAS AF: 0.0671

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.198

Alfa AF: 0.198 Hom.: 2325

Bravo AF: 0.197

TwinsUK AF: 0.211 AC: 781

ALSPAC AF: 0.214 AC: 826

ESP6500AA AF: 0.227 AC: 1001

ESP6500EA AF: 0.200 AC: 1718

ExAC AF: 0.176 AC: 21324

Asia WGS AF: 0.0730 AC: 254 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.199

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.010
Dann	Benign	0.28
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.43	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.058
Sift	Benign	0.62	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.026
MutPred		0.15		Gain of helix (P = 0.0325);
MPC		0.36
ClinPred		0.0053	T
GERP RS		-12
Varity_R		0.034
gMVP		0.049

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: rs10889205; hg19: chr1-40705726; COSMIC: COSV65650679;