12-132853572-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001161346.2(CHFR):c.1231C>T(p.Gln411Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,376,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CHFR NM_001161346.2 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9725
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.23

Genes affected

CHFR (HGNC:20455): (checkpoint with forkhead and ring finger domains) This gene encodes an E3 ubiquitin-protein ligase required for the maintenance of the antephase checkpoint that regulates cell cycle entry into mitosis and, therefore, may play a key role in cell cycle progression and tumorigenesis. The encoded protein has an N-terminal forkhead-associated domain, a central RING-finger domain, and a cysteine-rich C-terminal region. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001161346.2 Downstream stopcodon found after 6 codons.
• PP5: Variant 12-132853572-G-A is Pathogenic according to our data. Variant chr12-132853572-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1802254.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHFR	NM_001161346.2	c.1231C>T	p.Gln411Ter	stop_gained, splice_region_variant	11/18	ENST00000450056.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHFR	ENST00000450056.7	c.1231C>T	p.Gln411Ter	stop_gained, splice_region_variant	11/18	2	NM_001161346.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1376388 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 679378

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: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Oct 12, 2022

Although the CHFR gene (MIM*605209) has not been associated with any disease in OMIM, scientific research suggests that it is a tumor suppressor gene (PMID: 15793587) that has been implicated in a wide range of cancers, in published studies (PMID: 22159584). The c.1231C>T variant is not present in publicly available population databases like 1000 Genomes, ExAC, EVS, gnomAD, Indian Exome Database or our in-house exome database. The variant has neither been published nor reported to ClinVar, HGMD or OMIM. In-silico pathogenicity prediction programs like MutationTaster, CADD, Varsome etc. predicted this variant to be likely deleterious. The variant creates a premature translational stop signal at the 411st amino acid position of the wild-type transcript, which may either result in translation of a truncated protein or cause nonsense mediated decay of the mRNA. The variant has also been predicted to affect splicing (splice-distance 2bp) by several computational splice-site effect prediction tools. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	49
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.82
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.040		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: chr12-133430158;