1-35736567-G-A

Variant names:

• chr1-35736567-G-A
• rs1381285618
• NM_022111.4:c.3949C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022111.4(CLSPN):​c.3949C>T​(p.Pro1317Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,470 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLSPN NM_022111.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

Genes affected

CLSPN (HGNC:19715): (claspin) The product of this gene is an essential upstream regulator of checkpoint kinase 1 and triggers a checkpoint arrest of the cell cycle in response to replicative stress or DNA damage. The protein is also required for efficient DNA replication during a normal S phase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21492824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLSPN	NM_022111.4	c.3949C>T	p.Pro1317Ser	missense_variant	Exon 25 of 25	ENST00000318121.8	NP_071394.2
CLSPN	NM_001190481.2	c.3757C>T	p.Pro1253Ser	missense_variant	Exon 24 of 24		NP_001177410.1
CLSPN	NM_001330490.2	c.3909+347C>T		intron_variant	Intron 24 of 24		NP_001317419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLSPN	ENST00000318121.8	c.3949C>T	p.Pro1317Ser	missense_variant	Exon 25 of 25	1	NM_022111.4	ENSP00000312995.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460470 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726510

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3949C>T (p.P1317S) alteration is located in exon 25 (coding exon 25) of the CLSPN gene. This alteration results from a C to T substitution at nucleotide position 3949, causing the proline (P) at amino acid position 1317 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	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0088	T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	D;N;N
REVEL	Benign	0.099
Sift	Uncertain	0.016	D;D;T
Sift4G	Benign	0.071	T;T;T
Polyphen		0.98	D;D;.
Vest4		0.17
MutPred		0.14		Gain of phosphorylation at P1317 (P = 0.0205);.;.;
MVP		0.19
MPC		0.44
ClinPred		0.76	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1381285618; hg19: chr1-36202168;