17-40140775-A-T

Variant names:

• chr17-40140775-A-T
• rs1598417215
• NM_007359.5:c.227A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007359.5(CASC3):​c.227A>T​(p.Glu76Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000303 in 991,488 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: CASC3 NM_007359.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 0 publications found

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]

ENSG00000310351 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007359.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASC3	NM_007359.5	MANE Select	c.227A>T	p.Glu76Val	missense	Exon 1 of 14	NP_031385.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASC3	ENST00000264645.12	TSL:1 MANE Select	c.227A>T	p.Glu76Val	missense	Exon 1 of 14	ENSP00000264645.6	O15234
	CASC3	ENST00000418132.7	TSL:1	n.458A>T		non_coding_transcript_exon	Exon 1 of 8
	CASC3	ENST00000971362.1		c.227A>T	p.Glu76Val	missense	Exon 1 of 14	ENSP00000641421.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000303 AC: 3 AN: 991488 Hom.: 0 Cov.: 33 AF XY: 0.00000421 AC XY: 2 AN XY: 475498

African (AFR) AF: 0.00 AC: 0 AN: 19186

American (AMR) AF: 0.00 AC: 0 AN: 11274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9040

East Asian (EAS) AF: 0.00 AC: 0 AN: 8996

South Asian (SAS) AF: 0.00 AC: 0 AN: 54554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2170

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 831308

Other (OTH) AF: 0.0000294 AC: 1 AN: 34004

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.16		Loss of solvent accessibility (P = 0.0062)
MVP		0.38
MPC		1.9
ClinPred		0.94	D
GERP RS		4.9
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.64
gMVP		0.34
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1598417215; hg19: chr17-38297028;