9-39078834-C-T

Variant names:

• chr9-39078834-C-T
• rs1410147674
• NM_033655.5:c.3529G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033655.5(CNTNAP3):​c.3529G>A​(p.Ala1177Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A1177P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 47)
  • Exomes 𝑓: 0.0000036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.603
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19031247).

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.3529G>A	p.Ala1177Thr	missense	Exon 22 of 24	NP_387504.2
	CNTNAP3	NM_001393379.1		c.3286G>A	p.Ala1096Thr	missense	Exon 21 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.3529G>A	p.Ala1177Thr	missense	Exon 22 of 24	ENSP00000297668.6	Q9BZ76-1
	CNTNAP3	ENST00000377656.6	TSL:1	c.3286G>A	p.Ala1096Thr	missense	Exon 21 of 23	ENSP00000366884.2	A6NC89
	CNTNAP3	ENST00000865312.1		c.3649G>A	p.Ala1217Thr	missense	Exon 23 of 25	ENSP00000535371.1

Frequencies

GnomAD3 genomes Cov.: 47

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000362 AC: 5 AN: 1380842 Hom.: 0 Cov.: 175 AF XY: 0.00000587 AC XY: 4 AN XY: 681440

⚠️ 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: 31368

American (AMR) AF: 0.00 AC: 0 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25114

East Asian (EAS) AF: 0.00 AC: 0 AN: 35670

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078208

Other (OTH) AF: 0.0000173 AC: 1 AN: 57682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 47

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.043	N
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.60
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.13	T
Sift4G	Benign	0.27	T
Polyphen		0.36	B
Vest4		0.055
MutPred		0.40		Gain of phosphorylation at A1177 (P = 0.0068)
MVP		0.65
ClinPred		0.14	T
GERP RS		2.6
Varity_R		0.037
gMVP		0.24
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1410147674; hg19: chr9-39078831;