Genetic Variant NM_007359.5:c.175C>T (chr17-40140723-C-T) – 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.175C>T(p.Leu59Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 1,552,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

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:

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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=0.16459969).

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.175C>T	p.Leu59Phe	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.175C>T	p.Leu59Phe	missense	Exon 1 of 14	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7	TSL:1	n.406C>T		non_coding_transcript_exon	Exon 1 of 8
CASC3	ENST00000971362.1		c.175C>T	p.Leu59Phe	missense	Exon 1 of 14	ENSP00000641421.1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150846

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:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000196

AC:

AN:

152774

AF XY:

0.0000120

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:

0.00

Gnomad NFE exome

AF:

0.0000510

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000713

AC:

AN:

1402018

Hom.:

Cov.:

AF XY:

0.00000866

AC XY:

AN XY:

692470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31734

American (AMR)

AF:

0.00

AC:

AN:

34844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24708

East Asian (EAS)

AF:

0.00

AC:

AN:

36916

South Asian (SAS)

AF:

0.0000125

AC:

AN:

80226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4214

European-Non Finnish (NFE)

AF:

0.00000739

AC:

AN:

1083194

Other (OTH)

AF:

0.0000173

AC:

AN:

57936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.00000662

AC:

AN:

150954

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73712

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41114

American (AMR)

AF:

0.00

AC:

AN:

15064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.000210

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67790

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000938

AC:

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

Benign

0.085

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.081

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

3.1

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.32

REVEL

Benign

0.028

Sift

Benign

0.11

Sift4G

Benign

0.18

Polyphen

0.024

Vest4

0.35

MutPred

0.31

Loss of sheet (P = 0.0817)

MVP

0.13

MPC

1.9

ClinPred

0.57

GERP RS

3.9

PromoterAI

0.077

Neutral

(source)

Varity_R

0.068

gMVP

0.062

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over