Genetic Variant NM_007359.5:c.199G>T (chr17-40140747-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007359.5(CASC3):c.199G>T(p.Gly67Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,376,378 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. G67R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

Publications

0 publications found

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:

ENSG00000310351 (HGNC:):

ENSG00000310351 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.199G>T	p.Gly67Trp	missense	Exon 1 of 14	NP_031385.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASC3	ENST00000264645.12	TSL:1 MANE Select	c.199G>T	p.Gly67Trp	missense	Exon 1 of 14	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7	TSL:1	n.430G>T		non_coding_transcript_exon	Exon 1 of 8
CASC3	ENST00000971362.1		c.199G>T	p.Gly67Trp	missense	Exon 1 of 14	ENSP00000641421.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1376378

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

677360

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30826

American (AMR)

AF:

0.00

AC:

AN:

32900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23430

East Asian (EAS)

AF:

0.00

AC:

AN:

35726

South Asian (SAS)

AF:

0.00

AC:

AN:

75616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3978

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1070264

Other (OTH)

AF:

0.00

AC:

AN:

56944

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.82

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.81

PhyloP100

4.4

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.77

REVEL

Benign

0.18

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.41

MutPred

0.27

Loss of relative solvent accessibility (P = 0.0186)

MVP

0.34

MPC

2.0

ClinPred

0.99

GERP RS

4.7

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over