17-40140762-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007359.5(CASC3):​c.214G>T​(p.Ala72Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 28)

Consequence

CASC3
NM_007359.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.078525364).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASC3NM_007359.5 linkc.214G>T p.Ala72Ser missense_variant Exon 1 of 14 ENST00000264645.12 NP_031385.2
CASC3XM_005257163.3 linkc.214G>T p.Ala72Ser missense_variant Exon 1 of 14 XP_005257220.1 O15234
CASC3XM_047435623.1 linkc.214G>T p.Ala72Ser missense_variant Exon 1 of 9 XP_047291579.1
CASC3XM_047435624.1 linkc.-752G>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.214G>T p.Ala72Ser missense_variant Exon 1 of 14 1 NM_007359.5 ENSP00000264645.6 O15234

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.214G>T (p.A72S) alteration is located in exon 1 (coding exon 1) of the CASC3 gene. This alteration results from a G to T substitution at nucleotide position 214, causing the alanine (A) at amino acid position 72 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.020
T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.063
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.72
T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.079
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.12
N
REVEL
Benign
0.039
Sift
Benign
0.35
T
Sift4G
Benign
0.41
T
Polyphen
0.14
B
Vest4
0.18
MutPred
0.11
Gain of phosphorylation at A72 (P = 0.0042);
MVP
0.27
MPC
1.7
ClinPred
0.54
D
GERP RS
3.7
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.066
gMVP
0.042

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38297015; API