9-39078887-G-A

Variant names:

• chr9-39078887-G-A
• rs1424023584
• NM_033655.5:c.3476C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033655.5(CNTNAP3):​c.3476C>T​(p.Ala1159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26703978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3476C>T	p.Ala1159Val	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3233C>T	p.Ala1078Val	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.3476C>T	p.Ala1159Val	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6
CNTNAP3	ENST00000377656.6	c.3233C>T	p.Ala1078Val	missense_variant	Exon 21 of 23	1		ENSP00000366884.2
CNTNAP3	ENST00000477002.1	n.222C>T		non_coding_transcript_exon_variant	Exon 3 of 3	5
CNTNAP3	ENST00000493965.5	n.274-431C>T		intron_variant	Intron 3 of 4	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1380858 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 681484

African (AFR) AF: 0.00 AC: 0 AN: 31304

American (AMR) AF: 0.00 AC: 0 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35614

South Asian (SAS) AF: 0.00 AC: 0 AN: 79100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33896

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078376

Other (OTH) AF: 0.00 AC: 0 AN: 57698

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

⚠️ 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: 41472

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

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

⚠️ 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3476C>T (p.A1159V) alteration is located in exon 22 (coding exon 22) of the CNTNAP3 gene. This alteration results from a C to T substitution at nucleotide position 3476, causing the alanine (A) at amino acid position 1159 to be replaced by a valine (V). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		3.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.27
Sift	Benign	0.49	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.88	P;P
Vest4		0.11
MutPred		0.60		Loss of disorder (P = 0.0726);.;
MVP		0.66
ClinPred		0.62	D
GERP RS		2.6
Varity_R		0.088
gMVP		0.20
Mutation Taster		=95/5	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: rs1424023584; hg19: chr9-39078884;