Genetic Variant CLASRP:p.Ser400Phe (chr19-45064420-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007056.3(CLASRP):c.1199C>T(p.Ser400Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

CLASRP
NM_007056.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.487

Publications

0 publications found

Variant links:

Genes affected

CLASRP (HGNC:17731): (CLK4 associating serine/arginine rich protein) Predicted to be involved in RNA splicing and mRNA processing. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CLASRP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17490879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLASRP	NM_007056.3 link	c.1199C>T	p.Ser400Phe	missense_variant	Exon 13 of 21	ENST00000221455.8	NP_008987.2	Q8N2M8A0A0A0MQS2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLASRP	ENST00000221455.8 link	c.1199C>T	p.Ser400Phe	missense_variant	Exon 13 of 21	1	NM_007056.3	ENSP00000221455.3	A0A0A0MQS2
CLASRP	ENST00000391952.7 link	n.1199C>T		non_coding_transcript_exon_variant	Exon 13 of 21	1		ENSP00000375814.2	Q8N2M8
CLASRP	ENST00000544944.6 link	c.1199C>T	p.Ser400Phe	missense_variant	Exon 12 of 19	2		ENSP00000438702.1	F5H0Q6
CLASRP	ENST00000391953.8 link	c.1013C>T	p.Ser338Phe	missense_variant	Exon 12 of 20	2		ENSP00000375815.3	Q8N2M8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.26e-7

AC:

AN:

1377268

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

680006

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:

31410

American (AMR)

AF:

0.00

AC:

AN:

35580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25044

East Asian (EAS)

AF:

0.00

AC:

AN:

35616

South Asian (SAS)

AF:

0.00

AC:

AN:

79022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1072210

Other (OTH)

AF:

0.00

AC:

AN:

57518

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1199C>T (p.S400F) alteration is located in exon 13 (coding exon 12) of the CLASRP gene. This alteration results from a C to T substitution at nucleotide position 1199, causing the serine (S) at amino acid position 400 to be replaced by a phenylalanine (F). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

T;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.83

T;.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.49

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.013

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.0

.;.;B

Vest4

0.38

MutPred

0.32

Loss of phosphorylation at S400 (P = 0);.;Loss of phosphorylation at S400 (P = 0);

MVP

0.25

MPC

0.80

ClinPred

0.83

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.55

Mutation Taster

=79/21

polymorphism

(source)

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

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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