Genetic Variant NM_033655.5:c.3668G>T (chr9-39078695-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033655.5(CNTNAP3):c.3668G>T(p.Gly1223Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 50)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CNTNAP3
NM_033655.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.84

Publications

0 publications found

Variant links:

Genes affected

CNTNAP3 (HGNC:13834): (contactin associated protein family member 3) The protein encoded by this gene belongs to the NCP family of cell-recognition molecules. This family represents a distinct subgroup of the neurexins. NCP proteins mediate neuron-glial interactions in vertebrates and glial-glial contact in invertebrates. The protein encoded by this gene may play a role in cell recognition within the nervous system. Alternatively spliced transcript variants encoding different isoforms have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

CNTNAP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10338643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5 link	c.3668G>T	p.Gly1223Val	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2	Q9BZ76-1
CNTNAP3	NM_001393379.1 link	c.3425G>T	p.Gly1142Val	missense_variant	Exon 21 of 23		NP_001380308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTNAP3	ENST00000297668.11 link	c.3668G>T	p.Gly1223Val	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6	Q9BZ76-1
CNTNAP3	ENST00000377656.6 link	c.3425G>T	p.Gly1142Val	missense_variant	Exon 21 of 23	1		ENSP00000366884.2	A6NC89
CNTNAP3	ENST00000493965.5 link	n.274-239G>T		intron_variant	Intron 3 of 4	5
CNTNAP3	ENST00000477002.1 link	n.*123G>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1384300

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

682562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30820

American (AMR)

AF:

0.00

AC:

AN:

31776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24802

East Asian (EAS)

AF:

0.00

AC:

AN:

35634

South Asian (SAS)

AF:

0.00

AC:

AN:

77052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3990

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075966

Other (OTH)

AF:

0.0000175

AC:

AN:

57302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3668G>T (p.G1223V) alteration is located in exon 22 (coding exon 22) of the CNTNAP3 gene. This alteration results from a G to T substitution at nucleotide position 3668, causing the glycine (G) at amino acid position 1223 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.0045

BayesDel_noAF

Benign

-0.24

CADD

Benign

9.2

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0028

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.9

L;.

PhyloP100

1.8

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.21

Sift

Benign

0.51

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.025

B;P

Vest4

0.34

MutPred

0.28

Loss of sheet (P = 0.0228);.;

MVP

0.69

ClinPred

0.12

GERP RS

0.57

Varity_R

0.037

gMVP

0.40

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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NM_033655.5:c.3668G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over