17-40163592-G-T

Variant names:

• chr17-40163592-G-T
• rs201628547
• NM_007359.5:c.897G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007359.5(CASC3):​c.897G>T​(p.Arg299Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CASC3 NM_007359.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.386

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC3	NM_007359.5	c.897G>T	p.Arg299Ser	missense_variant	Exon 7 of 14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3	c.897G>T	p.Arg299Ser	missense_variant	Exon 7 of 14		XP_005257220.1
CASC3	XM_047435623.1	c.897G>T	p.Arg299Ser	missense_variant	Exon 7 of 9		XP_047291579.1
CASC3	XM_047435624.1	c.-22G>T		5_prime_UTR_variant	Exon 8 of 15		XP_047291580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASC3	ENST00000264645.12	c.897G>T	p.Arg299Ser	missense_variant	Exon 7 of 14	1	NM_007359.5	ENSP00000264645.6
CASC3	ENST00000418132.7	n.1128G>T		non_coding_transcript_exon_variant	Exon 7 of 8	1
CASC3	ENST00000474190.1	n.555G>T		non_coding_transcript_exon_variant	Exon 4 of 6	3		ENSP00000462713.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Benign	0.85
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.39	T
Polyphen		0.99	D
Vest4		0.62
MutPred		0.58		Loss of methylation at R299 (P = 0.0184);
MVP		0.67
MPC		0.68
ClinPred		0.72	D
GERP RS		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs201628547; hg19: chr17-38319845;