1-40236196-A-C

Variant names:

• chr1-40236196-A-C
• NM_012421.4:c.1494A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012421.4(RLF):​c.1494A>C​(p.Glu498Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RLF NM_012421.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1663655).

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.1494A>C	p.Glu498Asp	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.1494A>C	p.Glu498Asp	missense	Exon 8 of 8	ENSP00000361857.4	Q13129

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0033	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.035
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.52	P
Vest4		0.21
MutPred		0.30		Loss of catalytic residue at E498 (P = 0.1384)
MVP		0.64
MPC		0.37
ClinPred		0.54	D
GERP RS		5.0
Varity_R		0.077
gMVP		0.14
Mutation Taster		=96/4	polymorphism

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

hg19: chr1-40701868;