Genetic Variant CSN1S1:p.Ile155Asn (chr4-69944911-T-A) – 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_001890.2(CSN1S1):c.464T>A(p.Ile155Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CSN1S1
NM_001890.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.11

Publications

0 publications found

Variant links:

Genes affected

CSN1S1 (HGNC:2445): (casein alpha s1) Predicted to be involved in response to dehydroepiandrosterone; response to estradiol; and response to steroid hormone. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

CSN1S1 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=0.08235878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2 link	c.464T>A	p.Ile155Asn	missense_variant	Exon 15 of 16	ENST00000246891.9	NP_001881.1	P47710-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN1S1	ENST00000246891.9 link	c.464T>A	p.Ile155Asn	missense_variant	Exon 15 of 16	1	NM_001890.2	ENSP00000246891.4		P47710-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111294

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00000378

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.464T>A (p.I155N) alteration is located in exon 15 (coding exon 14) of the CSN1S1 gene. This alteration results from a T to A substitution at nucleotide position 464, causing the isoleucine (I) at amino acid position 155 to be replaced by an asparagine (N). 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

0.20

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

4.2

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.082

T;.;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.76

T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.082

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.;.;.

PhyloP100

-1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.18

T;T;D;T;D

Sift4G

Benign

0.43

T;T;T;T;T

Polyphen

0.23

B;.;B;.;.

Vest4

0.46

MutPred

0.32

Gain of sheet (P = 0.0827);.;.;.;.;

MVP

0.085

MPC

0.27

ClinPred

0.63

GERP RS

-5.6

Varity_R

0.064

gMVP

0.069

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