Genetic Variant CASC3:p.Glu74Ala (chr17-40140769-A-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007359.5(CASC3):c.221A>C(p.Glu74Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,169,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E74D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.79

Publications

1 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.11215335).

BS2

High AC in GnomAd4 at 12 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.221A>C	p.Glu74Ala	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.221A>C	p.Glu74Ala	missense	Exon 1 of 14	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7	TSL:1	n.452A>C		non_coding_transcript_exon	Exon 1 of 8
CASC3	ENST00000971362.1		c.221A>C	p.Glu74Ala	missense	Exon 1 of 14	ENSP00000641421.1

Frequencies

GnomAD3 genomes

AF:

0.000121

AC:

AN:

99416

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000627

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000576

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000202

AC:

AN:

79392

AF XY:

0.000212

show subpopulations

Gnomad AFR exome

AF:

0.000218

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000797

Gnomad NFE exome

AF:

0.000152

Gnomad OTH exome

AF:

0.000440

GnomAD4 exome

AF:

0.000117

AC:

125

AN:

1070112

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

517730

show subpopulations

African (AFR)

AF:

0.000138

AC:

AN:

21722

American (AMR)

AF:

0.00

AC:

AN:

19052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11498

East Asian (EAS)

AF:

0.00

AC:

AN:

11334

South Asian (SAS)

AF:

0.0000466

AC:

AN:

64314

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

23066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2426

European-Non Finnish (NFE)

AF:

0.0000774

AC:

AN:

879048

Other (OTH)

AF:

0.000345

AC:

AN:

37652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000121

AC:

AN:

99416

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

45770

show subpopulations

African (AFR)

AF:

0.000118

AC:

AN:

25502

American (AMR)

AF:

0.00

AC:

AN:

7288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2830

East Asian (EAS)

AF:

0.000627

AC:

AN:

3190

South Asian (SAS)

AF:

0.00

AC:

AN:

2698

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

3534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

52100

Other (OTH)

AF:

0.00

AC:

AN:

1312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.00

Hom.:

ExAC

AF:

0.0000325

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.0

PhyloP100

5.8

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.7

REVEL

Benign

0.082

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.013

Polyphen

0.73

Vest4

0.36

MVP

0.28

MPC

1.8

ClinPred

0.40

GERP RS

4.9

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.13

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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