18-641341-C-A

Variant summary

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

The NM_001393344.1(CLUL1):c.1009C>A(p.Pro337Thr) 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 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLUL1 NM_001393344.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

Genes affected

CLUL1 (HGNC:2096): (clusterin like 1)

TYMSOS (HGNC:29553): (TYMS opposite strand RNA)

LOC105371952 (HGNC:):

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=0.3207417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLUL1	NM_001393344.1	c.1009C>A	p.Pro337Thr	missense_variant	8/10	ENST00000692774.1
LOC105371952	XR_935082.4	n.3373G>T		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLUL1	ENST00000692774.1	c.1009C>A	p.Pro337Thr	missense_variant	8/10		NM_001393344.1	P1
TYMSOS	ENST00000585033.1	n.539G>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 09, 2021

The c.1009C>A (p.P337T) alteration is located in exon 7 (coding exon 6) of the CLUL1 gene. This alteration results from a C to A substitution at nucleotide position 1009, causing the proline (P) at amino acid position 337 to be replaced by a threonine (T). 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	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.035	T;T;.;T;T;T
Eigen	Benign	0.010
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D;D;.;.;D;.
REVEL	Benign	0.18
Sift	Benign	0.034	D;T;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D
Vest4		0.38
MutPred		0.33		.;Gain of phosphorylation at P389 (P = 0.08);.;Gain of phosphorylation at P389 (P = 0.08);.;.;
MVP		0.13
MPC		0.82
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.094
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr18-641341;