17-40140769-A-T

Variant summary

Our verdict is Likely benign. Variant got -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.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 24)
Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

2
6
11

Clinical Significance

Not reported in ClinVar

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASC3NM_007359.5 linkc.221A>T p.Glu74Val missense_variant Exon 1 of 14 ENST00000264645.12 NP_031385.2
CASC3XM_005257163.3 linkc.221A>T p.Glu74Val missense_variant Exon 1 of 14 XP_005257220.1 O15234
CASC3XM_047435623.1 linkc.221A>T p.Glu74Val missense_variant Exon 1 of 9 XP_047291579.1
CASC3XM_047435624.1 linkc.-745A>T 5_prime_UTR_variant Exon 1 of 15 XP_047291580.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CASC3ENST00000264645.12 linkc.221A>T p.Glu74Val missense_variant Exon 1 of 14 1 NM_007359.5 ENSP00000264645.6 O15234

Frequencies

GnomAD3 genomes
AF:
0.000101
AC:
10
AN:
99416
Hom.:
0
Cov.:
24
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
GnomAD3 exomes
AF:
0.0000378
AC:
3
AN:
79392
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
42364
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 SAS 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.:
0
Cov.:
33
AF XY:
0.0000927
AC XY:
48
AN XY:
517712
show subpopulations
Gnomad4 AFR exome
AF:
0.0000460
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000882
Gnomad4 SAS exome
AF:
0.000218
Gnomad4 FIN exome
AF:
0.0000434
Gnomad4 NFE exome
AF:
0.0000853
Gnomad4 OTH exome
AF:
0.000212
GnomAD4 genome
AF:
0.000101
AC:
10
AN:
99416
Hom.:
0
Cov.:
24
AF XY:
0.0000437
AC XY:
2
AN XY:
45770
show subpopulations
Gnomad4 AFR
AF:
0.0000392
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000371
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000154
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000325
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Benign
0.067
T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.75
T
M_CAP
Pathogenic
0.70
D
MetaRNN
Benign
0.31
T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.0
L
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.14
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.95
P
Vest4
0.41
MutPred
0.33
Gain of sheet (P = 0.0016);
MVP
0.30
MPC
1.9
ClinPred
0.74
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.44
gMVP
0.25

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

LitVar

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

Other links and lift over

dbSNP: rs766998291; hg19: chr17-38297022; API