9-39086849-C-A

Variant names:

• chr9-39086849-C-A
• rs1826073512
• NM_033655.5:c.3221G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033655.5(CNTNAP3):​c.3221G>T​(p.Gly1074Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: CNTNAP3 NM_033655.5 missense, splice_region
• Scores: Splicing: ADA: 0.9628
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033655.5. 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
	CNTNAP3	NM_033655.5	MANE Select	c.3221G>T	p.Gly1074Val	missense splice_region	Exon 20 of 24	NP_387504.2
	CNTNAP3	NM_001393379.1		c.2978G>T	p.Gly993Val	missense splice_region	Exon 19 of 23	NP_001380308.1	A6NC89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP3	ENST00000297668.11	TSL:1 MANE Select	c.3221G>T	p.Gly1074Val	missense splice_region	Exon 20 of 24	ENSP00000297668.6	Q9BZ76-1
	CNTNAP3	ENST00000377656.6	TSL:1	c.2978G>T	p.Gly993Val	missense splice_region	Exon 19 of 23	ENSP00000366884.2	A6NC89
	CNTNAP3	ENST00000865312.1		c.3341G>T	p.Gly1114Val	missense splice_region	Exon 21 of 25	ENSP00000535371.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.89		Gain of loop (P = 0.0435)
MVP		0.91
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.81
gMVP		0.70
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 0

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

Other links and lift over

dbSNP: rs1826073512; hg19: chr9-39086846;