1-10434664-T-G

Position:

• chr1-10434664-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000309048.8(CENPS):​c.183T>G​(p.Phe61Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CENPS ENST00000309048.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.899

Genes affected

CENPS (HGNC:23163): (centromere protein S) This gene was identified in the neuroblastoma tumor suppressor candidate region on chromosome 1p36. It contains a TFIID-31 domain, similar to that found in TATA box-binding protein-associated factor, TAF(II)31, which is required for p53-mediated transcription activation. This gene was expressed at very low levels in neuroblastoma tumors, and was shown to reduce cell growth in neuroblastoma cells, suggesting that it may have a role in a cell death pathway. The protein is a component of multiple complexes, including the Fanconi anemia (FA) core complex, the APITD1/CENPS complex, and the CENPA-CAD (nucleosome distal) complex. Known functions include an involvement with chromatin associations of the FA core complex, and a role in the stable assembly of the outer kinetochore. Alternative splicing of this gene results in multiple transcript variants. Naturally occurring read-through transcripts also exist between this gene and the downstream cortistatin (CORT) gene, as represented in GeneID:100526739. An APITD1-related pseudogene has been identified on chromosome 7. [provided by RefSeq, Nov 2010]

CENPS-CORT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3111726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPS	NM_199294.3	c.183T>G	p.Phe61Leu	missense_variant	3/5	ENST00000309048.8	NP_954988.1
CENPS-CORT	NR_037187.2	n.652+3263T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPS	ENST00000309048.8	c.183T>G	p.Phe61Leu	missense_variant	3/5	1	NM_199294.3	ENSP00000308583	P1
CENPS	ENST00000462462.1	c.112+3263T>G		intron_variant		3		ENSP00000489524
CENPS	ENST00000477755.1	c.*7T>G		3_prime_UTR_variant, NMD_transcript_variant	3/5	2		ENSP00000468629

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 07, 2024

The c.183T>G (p.F61L) alteration is located in exon 3 (coding exon 3) of the APITD1-CORT gene. This alteration results from a T to G substitution at nucleotide position 183, causing the phenylalanine (F) at amino acid position 61 to be replaced by a leucine (L). 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	0.95
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;.;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;D;D;T;.
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	.;.;.;.;L
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.0	D;D;.;.;D
REVEL	Benign	0.22
Sift	Benign	0.72	T;T;.;.;T
Sift4G	Benign	0.10	T;T;T;D;T
Polyphen		0.99	.;.;.;.;D
Vest4		0.73
MutPred		0.37		Loss of methylation at K63 (P = 0.1091);Loss of methylation at K63 (P = 0.1091);Loss of methylation at K63 (P = 0.1091);.;Loss of methylation at K63 (P = 0.1091);
MVP		0.014
MPC		0.025
ClinPred		0.84	D
GERP RS		4.2
Varity_R		0.70
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-10494721;