Genetic Variant NM_007359.5:c.227A>C (chr17-40140775-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -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

Publications

0 publications found

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:

ENSG00000310351 (HGNC:):

ENSG00000310351 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007359.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASC3	NM_007359.5	MANE Select	c.227A>C	p.Glu76Ala	missense	Exon 1 of 14	NP_031385.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASC3	ENST00000264645.12	TSL:1 MANE Select	c.227A>C	p.Glu76Ala	missense	Exon 1 of 14	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7	TSL:1	n.458A>C		non_coding_transcript_exon	Exon 1 of 8
CASC3	ENST00000971362.1		c.227A>C	p.Glu76Ala	missense	Exon 1 of 14	ENSP00000641421.1

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

African (AFR)

AF:

0.00

AC:

AN:

19186

American (AMR)

AF:

0.00

AC:

AN:

11274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9040

East Asian (EAS)

AF:

0.00

AC:

AN:

8996

South Asian (SAS)

AF:

0.0000183

AC:

AN:

54554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2170

European-Non Finnish (NFE)

AF:

0.00000722

AC:

AN:

831308

Other (OTH)

AF:

0.0000882

AC:

AN:

34004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000127

AC:

AN:

78500

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

35512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19964

American (AMR)

AF:

0.00

AC:

AN:

5120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2340

East Asian (EAS)

AF:

0.00

AC:

AN:

2458

South Asian (SAS)

AF:

0.000478

AC:

AN:

2094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

42668

Other (OTH)

AF:

0.00

AC:

AN:

1044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000518

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

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

PhyloP100

5.8

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

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.51

gMVP

0.20

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over