1-10440352-C-G

Variant names:

• chr1-10440352-C-G
• rs759332241
• NM_199294.3:c.215C>G

Variant summary

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

The NM_199294.3(CENPS):​c.215C>G​(p.Ala72Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A72V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: CENPS NM_199294.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53

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=0.36479583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPS	NM_199294.3	c.215C>G	p.Ala72Gly	missense_variant	Exon 4 of 5	ENST00000309048.8	NP_954988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPS	ENST00000309048.8	c.215C>G	p.Ala72Gly	missense_variant	Exon 4 of 5	1	NM_199294.3	ENSP00000308583.2
CENPS-CORT	ENST00000602787.6	c.215C>G	p.Ala72Gly	missense_variant	Exon 4 of 6	3		ENSP00000473509.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250500 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135446

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.86	D;T;D;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Uncertain	-0.048	T
MutationAssessor	Uncertain	2.8	.;.;.;M
PROVEAN	Uncertain	-2.6	D;.;.;D
REVEL	Pathogenic	0.67
Sift	Benign	0.046	D;.;.;D
Sift4G	Uncertain	0.046	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.41
MutPred		0.69		Loss of stability (P = 0.0789);Loss of stability (P = 0.0789);.;Loss of stability (P = 0.0789);
MVP		0.048
MPC		0.072
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.73
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759332241; hg19: chr1-10500409;