9-39078770-G-A

Variant names:

• chr9-39078770-G-A
• NM_033655.5:c.3593C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033655.5(CNTNAP3):​c.3593C>T​(p.Ala1198Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000293 in 1,365,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 40)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06234601).

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.3593C>T	p.Ala1198Val	missense	Exon 22 of 24	NP_387504.2
	CNTNAP3	NM_001393379.1		c.3350C>T	p.Ala1117Val	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.3593C>T	p.Ala1198Val	missense	Exon 22 of 24	ENSP00000297668.6	Q9BZ76-1
	CNTNAP3	ENST00000377656.6	TSL:1	c.3350C>T	p.Ala1117Val	missense	Exon 21 of 23	ENSP00000366884.2	A6NC89
	CNTNAP3	ENST00000865312.1		c.3713C>T	p.Ala1238Val	missense	Exon 23 of 25	ENSP00000535371.1

Frequencies

GnomAD3 genomes Cov.: 40

GnomAD4 exome AF: 0.00000293 AC: 4 AN: 1365406 Hom.: 0 Cov.: 92 AF XY: 0.00000297 AC XY: 2 AN XY: 673140

⚠️ 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: 30086

American (AMR) AF: 0.00 AC: 0 AN: 32834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23892

East Asian (EAS) AF: 0.00 AC: 0 AN: 34968

South Asian (SAS) AF: 0.00 AC: 0 AN: 76536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00000373 AC: 4 AN: 1071744

Other (OTH) AF: 0.00 AC: 0 AN: 56948

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 40

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	Benign	0.095
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.6
DANN	Benign	0.79
DEOGEN2	Benign	0.00031	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.64	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.17	N
REVEL	Benign	0.14
Sift	Benign	0.92	T
Sift4G	Benign	0.69	T
Polyphen		0.0040	B
Vest4		0.057
MutPred		0.27		Gain of sheet (P = 0.0827)
MVP		0.38
ClinPred		0.031	T
GERP RS		1.7
Varity_R		0.021
gMVP		0.22
Mutation Taster		=92/8	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

hg19: chr9-39078767;