1-35737410-T-A

Variant names:

• chr1-35737410-T-A
• rs140581594
• NM_022111.4:c.3676A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022111.4(CLSPN):​c.3676A>T​(p.Met1226Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. M1226V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLSPN NM_022111.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0310
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03605789).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022111.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLSPN	NM_022111.4	MANE Select	c.3676A>T	p.Met1226Leu	missense	Exon 23 of 25	NP_071394.2
	CLSPN	NM_001330490.2		c.3676A>T	p.Met1226Leu	missense	Exon 23 of 25	NP_001317419.1	Q9HAW4-3
	CLSPN	NM_001190481.2		c.3484A>T	p.Met1162Leu	missense	Exon 22 of 24	NP_001177410.1	Q9HAW4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLSPN	ENST00000318121.8	TSL:1 MANE Select	c.3676A>T	p.Met1226Leu	missense	Exon 23 of 25	ENSP00000312995.3	Q9HAW4-1
	CLSPN	ENST00000251195.9	TSL:1	c.3676A>T	p.Met1226Leu	missense	Exon 23 of 25	ENSP00000251195.5	Q9HAW4-3
	CLSPN	ENST00000520551.1	TSL:1	c.3517A>T	p.Met1173Leu	missense	Exon 23 of 25	ENSP00000428848.1	E7ESG2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461280 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111536

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.031
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.011
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.0010	B
Vest4		0.079
MutPred		0.28		Loss of MoRF binding (P = 0.0797)
MVP		0.15
MPC		0.079
ClinPred		0.011	T
GERP RS		-2.4
Varity_R		0.049
gMVP		0.084
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs140581594; hg19: chr1-36203011;