9-39085754-T-C

Variant names:

• chr9-39085754-T-C
• rs772812012
• NM_033655.5:c.3424A>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.3424A>G​(p.Ile1142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,556,582 control chromosomes in the GnomAD database, including 3 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 0.000021 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000029 (3 hom.)
• Consequence: CNTNAP3 NM_033655.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.268
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046050936).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5	c.3424A>G	p.Ile1142Val	missense_variant	Exon 21 of 24	ENST00000297668.11	NP_387504.2
CNTNAP3	NM_001393379.1	c.3181A>G	p.Ile1061Val	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.3424A>G	p.Ile1142Val	missense_variant	Exon 21 of 24	1	NM_033655.5	ENSP00000297668.6

Frequencies

GnomAD3 genomes AF: 0.0000210 AC: 3 AN: 142840 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000258

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: 0.0000308

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000332 AC: 8 AN: 240892 AF XY: 0.0000385

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000913

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000290 AC: 41 AN: 1413742 Hom.: 3 Cov.: 29 AF XY: 0.0000355 AC XY: 25 AN XY: 704072

African (AFR) AF: 0.00 AC: 0 AN: 32090

American (AMR) AF: 0.000113 AC: 5 AN: 44290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 37264

South Asian (SAS) AF: 0.0000362 AC: 3 AN: 82982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4006

European-Non Finnish (NFE) AF: 0.0000297 AC: 32 AN: 1077532

Other (OTH) AF: 0.0000172 AC: 1 AN: 58176

GnomAD4 genome AF: 0.0000210 AC: 3 AN: 142840 Hom.: 0 Cov.: 26 AF XY: 0.0000144 AC XY: 1 AN XY: 69368

African (AFR) AF: 0.0000258 AC: 1 AN: 38788

American (AMR) AF: 0.00 AC: 0 AN: 14642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4434

South Asian (SAS) AF: 0.00 AC: 0 AN: 4320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000308 AC: 2 AN: 64982

Other (OTH) AF: 0.00 AC: 0 AN: 1980

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3424A>G (p.I1142V) 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 3424, causing the isoleucine (I) at amino acid position 1142 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	Benign	0.091
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.2
DANN	Benign	0.31
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.47	N;.
PhyloP100		-0.27
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.35	N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.039
MutPred		0.60		Loss of catalytic residue at L1147 (P = 0.0763);.;
MVP		0.18
ClinPred		0.013	T
GERP RS		-5.8
Varity_R		0.027
gMVP		0.13
Mutation Taster		=91/9	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: rs772812012; hg19: chr9-39085751;