Genetic Variant NM_001010886.5:c.223G>A (chr6-35787867-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010886.5(CLPSL1):c.223G>A(p.Val75Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 41)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CLPSL1
NM_001010886.5 missense, splice_region

Scores

Splicing: ADA: 0.0002794

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.489

Publications

1 publications found

Variant links:

Genes affected

CLPSL1 (HGNC:21251): (colipase like 1) Predicted to enable enzyme activator activity. Predicted to be involved in response to food. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

CLPSL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.03437689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CLPSL1	NM_001010886.5 link	c.223G>A	p.Val75Met	missense_variant, splice_region_variant	Exon 3 of 3	ENST00000373861.6	NP_001010886.1
CLPSL1	XM_017010820.2 link	c.235G>A	p.Val79Met	missense_variant, splice_region_variant	Exon 2 of 2		XP_016866309.1
CLPSL1	NM_001348773.2 link	c.222+747G>A		intron_variant	Intron 2 of 2		NP_001335702.1
CLPSL1	XM_017010821.2 link	c.234+747G>A		intron_variant	Intron 1 of 1		XP_016866310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPSL1	ENST00000373861.6 link	c.223G>A	p.Val75Met	missense_variant, splice_region_variant	Exon 3 of 3	1	NM_001010886.5	ENSP00000362968.5		A2RUU4
CLPSL1	ENST00000428710.1 link	c.81+747G>A		intron_variant	Intron 1 of 1	3		ENSP00000396556.1		Q5T9G0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457590

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725304

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108710

Other (OTH)

AF:

0.00

AC:

AN:

60248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.223G>A (p.V75M) alteration is located in exon 3 (coding exon 3) of the CLPSL1 gene. This alteration results from a G to A substitution at nucleotide position 223, causing the valine (V) at amino acid position 75 to be replaced by a methionine (M). 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

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.5

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0061

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.25

M_CAP

Benign

0.0014

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

0.49

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.38

REVEL

Benign

0.010

Sift

Benign

0.045

Sift4G

Benign

0.074

Polyphen

0.0020

Vest4

0.030

MutPred

0.48

Loss of sheet (P = 0.0126);

MVP

0.072

MPC

0.042

ClinPred

0.076

GERP RS

0.0085

Varity_R

0.039

gMVP

0.29

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00028

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.33

Position offset: 0

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over