chr9-39078768-G-C

Variant names:

• chr9-39078768-G-C
• rs1335861574
• NM_033655.5:c.3595C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033655.5(CNTNAP3):​c.3595C>G​(p.Pro1199Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. P1199S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 40)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0776653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3595C>G	p.Pro1199Ala	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3352C>G	p.Pro1118Ala	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.3595C>G	p.Pro1199Ala	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6
CNTNAP3	ENST00000377656.6	c.3352C>G	p.Pro1118Ala	missense_variant	Exon 21 of 23	1		ENSP00000366884.2
CNTNAP3	ENST00000493965.5	n.274-312C>G		intron_variant	Intron 3 of 4	5
CNTNAP3	ENST00000477002.1	n.*50C>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1360344 Hom.: 0 Cov.: 93 AF XY: 0.00 AC XY: 0 AN XY: 670790

African (AFR) AF: 0.00 AC: 0 AN: 29598

American (AMR) AF: 0.00 AC: 0 AN: 30924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23550

East Asian (EAS) AF: 0.00 AC: 0 AN: 34824

South Asian (SAS) AF: 0.00 AC: 0 AN: 75902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3956

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070494

Other (OTH) AF: 0.00 AC: 0 AN: 56700

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 40 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

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

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00318 AC: 1 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.80
DANN	Benign	0.68
DEOGEN2	Benign	0.0049	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.61	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-1.1	N;.
PhyloP100		-0.12
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.10
Sift	Benign	0.20	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;B
Vest4		0.034
MutPred		0.35		Gain of sheet (P = 0.0344);.;
MVP		0.46
ClinPred		0.079	T
GERP RS		-1.1
Varity_R		0.024
gMVP		0.20
Mutation Taster		=95/5	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: rs1335861574; hg19: chr9-39078765;