1-40161488-C-T

Position:

• chr1-40161488-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012421.4(RLF):​c.89C>T​(p.Thr30Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RLF NM_012421.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18147486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLF	NM_012421.4	c.89C>T	p.Thr30Ile	missense_variant	1/8	ENST00000372771.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLF	ENST00000372771.5	c.89C>T	p.Thr30Ile	missense_variant	1/8	1	NM_012421.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446206 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The c.89C>T (p.T30I) alteration is located in exon 1 (coding exon 1) of the RLF gene. This alteration results from a C to T substitution at nucleotide position 89, causing the threonine (T) at amino acid position 30 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.98	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.087
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.32	B
Vest4		0.34
MutPred		0.20		Gain of sheet (P = 0.0221);
MVP		0.27
MPC		0.47
ClinPred		0.52	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-40627160;