12-132856579-A-C

Position:

• chr12-132856579-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001161346.2(CHFR):​c.1118T>G​(p.Ile373Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHFR NM_001161346.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHFR	NM_001161346.2	c.1118T>G	p.Ile373Ser	missense_variant	10/18	ENST00000450056.7	NP_001154818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHFR	ENST00000450056.7	c.1118T>G	p.Ile373Ser	missense_variant	10/18	2	NM_001161346.2	ENSP00000398735.2
CHFR	ENST00000315585.11	n.554T>G		non_coding_transcript_exon_variant	8/16	2		ENSP00000320557.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 20, 2023

The c.1031T>G (p.I344S) alteration is located in exon 10 (coding exon 9) of the CHFR gene. This alteration results from a T to G substitution at nucleotide position 1031, causing the isoleucine (I) at amino acid position 344 to be replaced by a serine (S). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	2.0	.;.;.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.4	.;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.82
MutPred		0.40		.;.;.;Loss of stability (P = 0.0072);
MVP		0.81
MPC		1.4
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.63

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: chr12-133433165;