Variant 17-40140775-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_007359.5(CASC3):c.227A>C(p.Glu76Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,069,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

Variant links:

Genes affected

CASC3 (HGNC:17040): (CASC3 exon junction complex subunit) The product of this gene is a core component of the exon junction complex (EJC), a protein complex that is deposited on spliced mRNAs at exon-exon junctions and functions in nonsense-mediated mRNA decay (NMD). The encoded protein binds RNA and interacts with two other EJC core components. It is predominantly located in the cytoplasm, but shuttles into the nucleus where it localizes to nuclear speckles. [provided by RefSeq, Jul 2008]

CASC3 links:

CASC3 (HGNC:):

CASC3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASC3	NM_007359.5 linkuse as main transcript	c.227A>C	p.Glu76Ala	missense_variant	1/14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3 linkuse as main transcript	c.227A>C	p.Glu76Ala	missense_variant	1/14		XP_005257220.1	O15234
CASC3	XM_047435623.1 linkuse as main transcript	c.227A>C	p.Glu76Ala	missense_variant	1/9		XP_047291579.1
CASC3	XM_047435624.1 linkuse as main transcript	c.-739A>C		5_prime_UTR_variant	1/15		XP_047291580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CASC3	ENST00000264645.12 linkuse as main transcript	c.227A>C	p.Glu76Ala	missense_variant	1/14	1	NM_007359.5	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7 linkuse as main transcript	n.458A>C		non_coding_transcript_exon_variant	1/8	1
CASC3	ENST00000581849.1 linkuse as main transcript	n.239A>C		non_coding_transcript_exon_variant	1/4	2
CASC3	ENST00000583649.1 linkuse as main transcript	n.232A>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000127

AC:

AN:

78500

Hom.:

Cov.:

show subpopulations

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:

0.000478

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

991488

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

475498

show subpopulations

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:

0.0000183

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000722

Gnomad4 OTH exome

AF:

0.0000882

GnomAD4 genome

AF:

0.0000127

AC:

AN:

78500

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

35512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000478

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000518

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.227A>C (p.E76A) alteration is located in exon 1 (coding exon 1) of the CASC3 gene. This alteration results from a A to C substitution at nucleotide position 227, causing the glutamic acid (E) at amino acid position 76 to be replaced by an alanine (A). 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

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.68

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.47

MutPred

0.13

Loss of solvent accessibility (P = 0.0062);

MVP

0.37

MPC

1.8

ClinPred

0.98

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.51

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over