dbSNP rs572418331: CSN1S1:c.106-4G>T (chr4-69935922-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001890.2(CSN1S1):c.106-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CSN1S1
NM_001890.2 splice_region, intron

Scores

Splicing: ADA: 0.00001582

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.96

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 4-69935922-G-T is Benign according to our data. Variant chr4-69935922-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 773695.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2 link	c.106-4G>T		splice_region_variant, intron_variant	Intron 4 of 15	ENST00000246891.9	NP_001881.1	P47710-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CSN1S1	ENST00000246891.9 link	c.106-4G>T	splice_region_variant, intron_variant	Intron 4 of 15	1	NM_001890.2	ENSP00000246891.4	P47710-1
CSN1S1	ENST00000507772.5 link	c.106-4G>T	splice_region_variant, intron_variant	Intron 3 of 13	5		ENSP00000427490.1	E9PDQ1
CSN1S1	ENST00000507763.5 link	c.106-4G>T	splice_region_variant, intron_variant	Intron 3 of 13	5		ENSP00000422611.1	P47710-4
CSN1S1	ENST00000505782.5 link	c.106-4G>T	splice_region_variant, intron_variant	Intron 3 of 12	5		ENSP00000426684.1	D6RF34

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149120

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000361

AC:

AN:

138372

AF XY:

0.0000275

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000125

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000543

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000246

AC:

AN:

1340142

Hom.:

Cov.:

AF XY:

0.0000241

AC XY:

AN XY:

662706

show subpopulations

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

African (AFR)

AF:

0.0000689

AC:

AN:

29028

American (AMR)

AF:

0.000331

AC:

AN:

30208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24284

East Asian (EAS)

AF:

0.0000578

AC:

AN:

34602

South Asian (SAS)

AF:

0.0000541

AC:

AN:

73906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49108

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5440

European-Non Finnish (NFE)

AF:

0.0000125

AC:

AN:

1037870

Other (OTH)

AF:

0.0000180

AC:

AN:

55696

⚠️ 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: 0.264

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

149120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72564

African (AFR)

AF:

0.00

AC:

AN:

40530

American (AMR)

AF:

0.00

AC:

AN:

15006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67274

Other (OTH)

AF:

0.00

AC:

AN:

2054

Alfa

AF:

0.000429

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.038

(source)

DANN

Benign

0.32

PhyloP100

-3.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.040

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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rs572418331

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over