chr17-40140770-G-T

Position:

chr17-40140770-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007359.5(CASC3):c.222G>T(p.Glu74Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,489,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.41

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]

CASC3 links:

CASC3 (HGNC:):

CASC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.096880615).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASC3	NM_007359.5 linkuse as main transcript	c.222G>T	p.Glu74Asp	missense_variant	1/14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3 linkuse as main transcript	c.222G>T	p.Glu74Asp	missense_variant	1/14		XP_005257220.1	O15234
CASC3	XM_047435623.1 linkuse as main transcript	c.222G>T	p.Glu74Asp	missense_variant	1/9		XP_047291579.1
CASC3	XM_047435624.1 linkuse as main transcript	c.-744G>T		5_prime_UTR_variant	1/15		XP_047291580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CASC3	ENST00000264645.12 linkuse as main transcript	c.222G>T	p.Glu74Asp	missense_variant	1/14	1	NM_007359.5	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7 linkuse as main transcript	n.453G>T		non_coding_transcript_exon_variant	1/8	1
CASC3	ENST00000581849.1 linkuse as main transcript	n.234G>T		non_coding_transcript_exon_variant	1/4	2
CASC3	ENST00000583649.1 linkuse as main transcript	n.227G>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150348

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

88166

Hom.:

AF XY:

0.00

AC XY:

AN XY:

46620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000345

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

1338696

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

655566

show subpopulations

Gnomad4 AFR exome

AF:

0.0000343

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:

0.0000161

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150348

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73386

show subpopulations

Gnomad4 AFR

AF:

0.0000245

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2024

The c.222G>T (p.E74D) 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 222, causing the glutamic acid (E) at amino acid position 74 to be replaced by an aspartic acid (D). 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

0.20

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Benign

-0.083

Eigen_PC

Benign

0.099

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.097

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.14

REVEL

Benign

0.040

Sift

Benign

0.079

Sift4G

Benign

0.12

Polyphen

0.0090

Vest4

0.25

MutPred

0.17

Loss of helix (P = 0.079);

MVP

0.29

MPC

1.6

ClinPred

0.80

GERP RS

4.9

Varity_R

0.28

gMVP

0.043

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over