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 NM_199294.3(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 NM_199294.3 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:38843): (CENPS-CORT readthrough) This locus represents naturally occurring read-through transcription between the neighboring APITD1 (apoptosis-inducing, TAF9-like domain 1) and CORT (cortistatin) genes. Alternative splicing results in multiple transcript variants, two of which encode fusion proteins that share sequence identity with the products of each individual gene. [provided by RefSeq, Aug 2011]

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

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	ENSP00000308583.2
CENPS-CORT	ENST00000602787.6	c.183T>G	p.Phe61Leu	missense_variant	3/6	3		ENSP00000473509.2

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
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;