NM_033655.5:c.3407A>G

Variant names:

• chr9-39085771-T-C
• rs181242281
• NM_033655.5:c.3407A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_033655.5(CNTNAP3):​c.3407A>G​(p.Asn1136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000956 in 1,568,846 control chromosomes in the GnomAD database, including 5 homozygotes. 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: 𝑓 0.00010 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000095 (5 hom.)
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04522389).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3407A>G	p.Asn1136Ser	missense_variant	Exon 21 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3164A>G	p.Asn1055Ser	missense_variant	Exon 20 of 23		NP_001380308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP3	ENST00000297668.11	c.3407A>G	p.Asn1136Ser	missense_variant	Exon 21 of 24	1	NM_033655.5	ENSP00000297668.6

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 15 AN: 146306 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000136

Gnomad OTH AF: 0.000497

GnomAD2 exomes AF: 0.000166 AC: 40 AN: 241324 AF XY: 0.000131

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.000470

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.0000949 AC: 135 AN: 1422424 Hom.: 5 Cov.: 31 AF XY: 0.0000875 AC XY: 62 AN XY: 708530

African (AFR) AF: 0.0000310 AC: 1 AN: 32210

American (AMR) AF: 0.000518 AC: 23 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25942

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38166

South Asian (SAS) AF: 0.00 AC: 0 AN: 83984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52284

Middle Eastern (MID) AF: 0.000495 AC: 2 AN: 4040

European-Non Finnish (NFE) AF: 0.0000822 AC: 89 AN: 1082816

Other (OTH) AF: 0.000307 AC: 18 AN: 58554

GnomAD4 genome AF: 0.000102 AC: 15 AN: 146422 Hom.: 0 Cov.: 28 AF XY: 0.0000843 AC XY: 6 AN XY: 71212

African (AFR) AF: 0.0000251 AC: 1 AN: 39794

American (AMR) AF: 0.000269 AC: 4 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 4766

South Asian (SAS) AF: 0.00 AC: 0 AN: 4468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000136 AC: 9 AN: 66384

Other (OTH) AF: 0.000492 AC: 1 AN: 2034

Alfa AF: 0.000136 Hom.: 1

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000830 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3407A>G (p.N1136S) alteration is located in exon 21 (coding exon 21) of the CNTNAP3 gene. This alteration results from a A to G substitution at nucleotide position 3407, causing the asparagine (N) at amino acid position 1136 to be replaced by a serine (S). 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	0.080
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.046	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		2.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.15
Sift	Benign	0.42	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.037	B;B
Vest4		0.31
MVP		0.63
ClinPred		0.024	T
GERP RS		2.1
Varity_R		0.070
gMVP		0.30
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs181242281; hg19: chr9-39085768;