Genetic Variant CSMD3:p.Asn3621Tyr (chr8-112228859-T-A) – 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_198123.2(CSMD3):c.10861A>T(p.Asn3621Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. N3621H) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CSMD3
NM_198123.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.26

Publications

30 publications found

Variant links:

Genes affected

CSMD3 (HGNC:19291): (CUB and Sushi multiple domains 3) Predicted to be involved in regulation of dendrite development. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CSMD3 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CSMD3 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_198123.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSMD3	NM_198123.2	MANE Select	c.10861A>T	p.Asn3621Tyr	missense	Exon 70 of 71	NP_937756.1	Q7Z407-1
CSMD3	NM_198124.2		c.10741A>T	p.Asn3581Tyr	missense	Exon 71 of 72	NP_937757.1	Q7Z407-2
CSMD3	NM_052900.3		c.10354A>T	p.Asn3452Tyr	missense	Exon 68 of 69	NP_443132.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSMD3	ENST00000297405.10	TSL:1 MANE Select	c.10861A>T	p.Asn3621Tyr	missense	Exon 70 of 71	ENSP00000297405.5	Q7Z407-1
CSMD3	ENST00000343508.7	TSL:1	c.10741A>T	p.Asn3581Tyr	missense	Exon 71 of 72	ENSP00000345799.3	Q7Z407-2
CSMD3	ENST00000455883.2	TSL:1	c.10354A>T	p.Asn3452Tyr	missense	Exon 68 of 69	ENSP00000412263.2	Q7Z407-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1425568

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711594

African (AFR)

AF:

0.00

AC:

AN:

32282

American (AMR)

AF:

0.00

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25902

East Asian (EAS)

AF:

0.00

AC:

AN:

39352

South Asian (SAS)

AF:

0.00

AC:

AN:

85440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080118

Other (OTH)

AF:

0.00

AC:

AN:

59030

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

131411

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Benign

0.0078

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

PhyloP100

4.3

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

REVEL

Benign

0.13

Sift

Benign

0.14

Sift4G

Benign

1.0

Polyphen

0.98

Vest4

0.55

MutPred

0.096

Gain of phosphorylation at N3621 (P = 0.0381)

MVP

0.17

MPC

0.54

ClinPred

0.92

GERP RS

5.6

Varity_R

0.12

gMVP

0.35

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over