chr1-40240054-A-T

Variant names:

• chr1-40240054-A-T
• rs10889205
• NM_012421.4:c.5352A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• 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.

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.5352A>T	p.Glu1784Asp	missense	Exon 8 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.5352A>T	p.Glu1784Asp	missense	Exon 8 of 8	ENSP00000361857.4	Q13129

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

GnomAD2 exomes AF: 0.176 AC: 44174 AN: 250630 AF XY: 0.171

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 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

African (AFR) AF: 0.237 AC: 7935 AN: 33472

American (AMR) AF: 0.165 AC: 7365 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3817 AN: 26132

East Asian (EAS) AF: 0.0742 AC: 2944 AN: 39688

South Asian (SAS) AF: 0.0761 AC: 6563 AN: 86246

European-Finnish (FIN) AF: 0.244 AC: 13014 AN: 53396

Middle Eastern (MID) AF: 0.147 AC: 848 AN: 5768

European-Non Finnish (NFE) AF: 0.209 AC: 232881 AN: 1111622

Other (OTH) AF: 0.180 AC: 10888 AN: 60386

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

African (AFR) AF: 0.239 AC: 9921 AN: 41510

American (AMR) AF: 0.155 AC: 2371 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 504 AN: 3468

East Asian (EAS) AF: 0.0571 AC: 296 AN: 5186

South Asian (SAS) AF: 0.0671 AC: 324 AN: 4826

European-Finnish (FIN) AF: 0.246 AC: 2607 AN: 10582

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14212 AN: 68000

Other (OTH) AF: 0.198 AC: 419 AN: 2112

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 v4.9

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
PhyloP100		-3.3
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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