20-49067246-A-T

Variant names:

• chr20-49067246-A-T
• rs1319510841
• NM_001316.4:c.533A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001316.4(CSE1L):​c.533A>T​(p.Asp178Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

Genes affected

CSE1L (HGNC:2431): (chromosome segregation 1 like) Proteins that carry a nuclear localization signal (NLS) are transported into the nucleus by the importin-alpha/beta heterodimer. Importin-alpha binds the NLS, while importin-beta mediates translocation through the nuclear pore complex. After translocation, RanGTP binds importin-beta and displaces importin-alpha. Importin-alpha must then be returned to the cytoplasm, leaving the NLS protein behind. The protein encoded by this gene binds strongly to NLS-free importin-alpha, and this binding is released in the cytoplasm by the combined action of RANBP1 and RANGAP1. In addition, the encoded protein may play a role both in apoptosis and in cell proliferation. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSE1L	NM_001316.4	c.533A>T	p.Asp178Val	missense_variant	Exon 6 of 25	ENST00000262982.3	NP_001307.2
CSE1L	NM_001362762.2	c.533A>T	p.Asp178Val	missense_variant	Exon 6 of 25		NP_001349691.1
CSE1L	NM_001256135.2	c.533A>T	p.Asp178Val	missense_variant	Exon 6 of 24		NP_001243064.1
CSE1L	NR_045796.2	n.301-1564A>T		intron_variant	Intron 3 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSE1L	ENST00000262982.3	c.533A>T	p.Asp178Val	missense_variant	Exon 6 of 25	1	NM_001316.4	ENSP00000262982.2
CSE1L	ENST00000396192.7	c.533A>T	p.Asp178Val	missense_variant	Exon 6 of 24	5		ENSP00000379495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250710 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135530

Gnomad AFR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.000164

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533A>T (p.D178V) alteration is located in exon 6 (coding exon 5) of the CSE1L gene. This alteration results from a A to T substitution at nucleotide position 533, causing the aspartic acid (D) at amino acid position 178 to be replaced by a valine (V). 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	0.61
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.99	.;D
Vest4		0.92
MutPred		0.71		Loss of ubiquitination at K174 (P = 0.0863);Loss of ubiquitination at K174 (P = 0.0863);
MVP		0.69
MPC		1.4
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1319510841; hg19: chr20-47683783;