17-40163615-T-C

Variant names:

• chr17-40163615-T-C
• NM_007359.5:c.920T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007359.5(CASC3):​c.920T>C​(p.Met307Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CASC3 NM_007359.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15093622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC3	NM_007359.5	c.920T>C	p.Met307Thr	missense_variant	Exon 7 of 14	ENST00000264645.12	NP_031385.2
CASC3	XM_047435624.1	c.2T>C	p.Met1?	start_lost	Exon 8 of 15		XP_047291580.1
CASC3	XM_005257163.3	c.920T>C	p.Met307Thr	missense_variant	Exon 7 of 14		XP_005257220.1
CASC3	XM_047435623.1	c.920T>C	p.Met307Thr	missense_variant	Exon 7 of 9		XP_047291579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASC3	ENST00000264645.12	c.920T>C	p.Met307Thr	missense_variant	Exon 7 of 14	1	NM_007359.5	ENSP00000264645.6
CASC3	ENST00000418132.7	n.1151T>C		non_coding_transcript_exon_variant	Exon 7 of 8	1
CASC3	ENST00000474190.1	n.565+13T>C		intron_variant	Intron 4 of 5	3		ENSP00000462713.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.920T>C (p.M307T) alteration is located in exon 7 (coding exon 7) of the CASC3 gene. This alteration results from a T to C substitution at nucleotide position 920, causing the methionine (M) at amino acid position 307 to be replaced by a threonine (T). 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	0.17
BayesDel_addAF	Benign	-0.0083	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.0045
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.047
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.67	T
Polyphen		0.073	B
Vest4		0.52
MutPred		0.23		Gain of glycosylation at M307 (P = 0.0154);
MVP		0.15
MPC		0.22
ClinPred		0.31	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr17-38319868;