chr17-40140762-G-T

Position:

• chr17-40140762-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 28)
• Consequence: CASC3 NM_007359.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
CASC3	NM_007359.5	c.214G>T	p.Ala72Ser	missense_variant	1/14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3	c.214G>T	p.Ala72Ser	missense_variant	1/14		XP_005257220.1
CASC3	XM_047435623.1	c.214G>T	p.Ala72Ser	missense_variant	1/9		XP_047291579.1
CASC3	XM_047435624.1	c.-752G>T		5_prime_UTR_variant	1/15		XP_047291580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASC3	ENST00000264645.12	c.214G>T	p.Ala72Ser	missense_variant	1/14	1	NM_007359.5	ENSP00000264645.6
CASC3	ENST00000418132.7	n.445G>T		non_coding_transcript_exon_variant	1/8	1
CASC3	ENST00000581849.1	n.226G>T		non_coding_transcript_exon_variant	1/4	2
CASC3	ENST00000583649.1	n.219G>T		non_coding_transcript_exon_variant	1/2	3

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

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;