Genetic Variant NM_007359.5:c.221A>T (chr17-40140769-A-T) – 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.221A>T(p.Glu74Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000941 in 1,169,498 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 0.00010 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000093 ( 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:

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 GnomAd4 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.221A>T	p.Glu74Val	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>T	p.Glu74Val	missense	Exon 1 of 14	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7	TSL:1	n.452A>T		non_coding_transcript_exon	Exon 1 of 8
CASC3	ENST00000971362.1		c.221A>T	p.Glu74Val	missense	Exon 1 of 14	ENSP00000641421.1

Frequencies

GnomAD3 genomes

AF:

0.000101

AC:

AN:

99416

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000392

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000371

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000154

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000378

AC:

AN:

79392

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000885

Gnomad NFE exome

AF:

0.0000759

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000935

AC:

100

AN:

1070082

Hom.:

Cov.:

AF XY:

0.0000927

AC XY:

AN XY:

517712

show subpopulations

African (AFR)

AF:

0.0000460

AC:

AN:

21720

American (AMR)

AF:

0.00

AC:

AN:

19050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11492

East Asian (EAS)

AF:

0.0000882

AC:

AN:

11334

South Asian (SAS)

AF:

0.000218

AC:

AN:

64312

European-Finnish (FIN)

AF:

0.0000434

AC:

AN:

23066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2426

European-Non Finnish (NFE)

AF:

0.0000853

AC:

AN:

879030

Other (OTH)

AF:

0.000212

AC:

AN:

37652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000101

AC:

AN:

99416

Hom.:

Cov.:

AF XY:

0.0000437

AC XY:

AN XY:

45770

show subpopulations

African (AFR)

AF:

0.0000392

AC:

AN:

25502

American (AMR)

AF:

0.00

AC:

AN:

7288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2830

East Asian (EAS)

AF:

0.00

AC:

AN:

3190

South Asian (SAS)

AF:

0.000371

AC:

AN:

2698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.000154

AC:

AN:

52100

Other (OTH)

AF:

0.00

AC:

AN:

1312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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

0.34

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.0

PhyloP100

5.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.1

REVEL

Benign

0.14

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.95

Vest4

0.41

MutPred

0.33

Gain of sheet (P = 0.0016)

MVP

0.30

MPC

1.9

ClinPred

0.74

GERP RS

4.9

PromoterAI

-0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.25

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.31

Position offset: -2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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