9-39078774-C-T

Variant names:

• chr9-39078774-C-T
• rs529451837
• NM_033655.5:c.3589G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033655.5(CNTNAP3):​c.3589G>A​(p.Val1197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,367,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. V1197L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 40)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.423
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3411013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3589G>A	p.Val1197Met	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3346G>A	p.Val1116Met	missense_variant	Exon 21 of 23		NP_001380308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP3	ENST00000297668.11	c.3589G>A	p.Val1197Met	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6
CNTNAP3	ENST00000377656.6	c.3346G>A	p.Val1116Met	missense_variant	Exon 21 of 23	1		ENSP00000366884.2
CNTNAP3	ENST00000493965.5	n.274-318G>A		intron_variant	Intron 3 of 4	5
CNTNAP3	ENST00000477002.1	n.*44G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 40

GnomAD4 exome AF: 0.00000366 AC: 5 AN: 1367550 Hom.: 0 Cov.: 92 AF XY: 0.00000445 AC XY: 3 AN XY: 674482

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

African (AFR) AF: 0.00 AC: 0 AN: 30114

American (AMR) AF: 0.00 AC: 0 AN: 33092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24086

East Asian (EAS) AF: 0.00 AC: 0 AN: 34940

South Asian (SAS) AF: 0.0000259 AC: 2 AN: 77268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3988

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1072738

Other (OTH) AF: 0.0000175 AC: 1 AN: 57008

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 40

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		0.42
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.16
MutPred		0.39		Gain of sheet (P = 0.0101);.;
MVP		0.69
ClinPred		0.41	T
GERP RS		2.6
Varity_R		0.065
gMVP		0.34
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs529451837; hg19: chr9-39078771;