Genetic Variant NM_007359.5:c.221A>G (chr17-40140769-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_007359.5(CASC3):c.221A>G(p.Glu74Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000667 in 1,169,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

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:

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=0.21066335).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC3	NM_007359.5 link	c.221A>G	p.Glu74Gly	missense_variant	Exon 1 of 14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3 link	c.221A>G	p.Glu74Gly	missense_variant	Exon 1 of 14		XP_005257220.1	O15234
CASC3	XM_047435623.1 link	c.221A>G	p.Glu74Gly	missense_variant	Exon 1 of 9		XP_047291579.1
CASC3	XM_047435624.1 link	c.-745A>G		5_prime_UTR_variant	Exon 1 of 15		XP_047291580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASC3	ENST00000264645.12 link	c.221A>G	p.Glu74Gly	missense_variant	Exon 1 of 14	1	NM_007359.5	ENSP00000264645.6		O15234

Frequencies

GnomAD3 genomes

AF:

0.0000503

AC:

AN:

99416

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000784

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:

0.0000576

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000126

AC:

AN:

79392

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

42364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000221

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000143

Gnomad SAS exome

AF:

0.0000899

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000682

AC:

AN:

1070112

Hom.:

Cov.:

AF XY:

0.0000502

AC XY:

AN XY:

517730

show subpopulations

Gnomad4 AFR exome

AF:

0.0000460

Gnomad4 AMR exome

AF:

0.000262

Gnomad4 ASJ exome

AF:

0.0000870

Gnomad4 EAS exome

AF:

0.0000882

Gnomad4 SAS exome

AF:

0.0000777

Gnomad4 FIN exome

AF:

0.0000434

Gnomad4 NFE exome

AF:

0.0000626

Gnomad4 OTH exome

AF:

0.0000797

GnomAD4 genome

AF:

0.0000503

AC:

AN:

99416

Hom.:

Cov.:

AF XY:

0.0000437

AC XY:

AN XY:

45770

show subpopulations

Gnomad4 AFR

AF:

0.0000784

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:

0.0000576

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000437

Hom.:

ExAC

AF:

0.0000325

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.221A>G (p.E74G) alteration is located in exon 1 (coding exon 1) of the CASC3 gene. This alteration results from a A to G substitution at nucleotide position 221, causing the glutamic acid (E) at amino acid position 74 to be replaced by a glycine (G). 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

0.28

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.8

REVEL

Benign

0.094

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.73

Vest4

0.39

MVP

0.21

MPC

1.9

ClinPred

0.23

GERP RS

4.9

Varity_R

0.30

gMVP

0.14

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