rs564609927

Variant names:

• chr9-39078705-G-A
• rs564609927
• NM_033655.5:c.3658C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-39078705-G-A
• chr9-39078705-G-C

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.3658C>T​(p.Leu1220Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,380,822 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. 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. L1220V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 49)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.752
• 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=0.13180363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3658C>T	p.Leu1220Phe	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3415C>T	p.Leu1139Phe	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.3658C>T	p.Leu1220Phe	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6
CNTNAP3	ENST00000377656.6	c.3415C>T	p.Leu1139Phe	missense_variant	Exon 21 of 23	1		ENSP00000366884.2
CNTNAP3	ENST00000493965.5	n.274-249C>T		intron_variant	Intron 3 of 4	5
CNTNAP3	ENST00000477002.1	n.*113C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152258 Hom.: 0 Cov.: 49

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1380822 Hom.: 0 Cov.: 64 AF XY: 0.00 AC XY: 0 AN XY: 680736

⚠️ 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: 30660

American (AMR) AF: 0.00 AC: 0 AN: 30826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24696

East Asian (EAS) AF: 0.00 AC: 0 AN: 35606

South Asian (SAS) AF: 0.00 AC: 0 AN: 76646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46202

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

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075048

Other (OTH) AF: 0.00 AC: 0 AN: 57150

⚠️ 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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152258 Hom.: 0 Cov.: 49 AF XY: 0.00 AC XY: 0 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.5
DANN	Benign	0.95
DEOGEN2	Benign	0.00040	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.50	T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.90	L;.
PhyloP100		0.75
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.17
Sift	Benign	0.75	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0	B;B
Vest4		0.041
MutPred		0.27		Gain of sheet (P = 0.0266);.;
MVP		0.71
ClinPred		0.053	T
GERP RS		0.70
Varity_R		0.039
gMVP		0.12
Mutation Taster		=91/9	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: rs564609927; hg19: chr9-39078702;