16-76452539-A-G

Variant names:

• chr16-76452539-A-G
• NM_033401.5:c.1103A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033401.5(CNTNAP4):​c.1103A>G​(p.Gln368Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP4 NM_033401.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50
• Publications: 0 publications found

Genes affected

CNTNAP4 (HGNC:18747): (contactin associated protein family member 4) This gene encodes a member of the neurexin protein family. Members of this family function in the vertebrate nervous system as cell adhesion molecules and receptors. This protein contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, and thrombospondin N-terminal-like domains. This protein may also play a role in proper neurotransmission in the dopaminergic and GABAergic systems and mutations in this gene may be associated with certain psychiatric illnesses. A polymorphism in an intron of this gene may be associated with longevity. [provided by RefSeq, Apr 2016]

ENSG00000287694 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP4	NM_033401.5	c.1103A>G	p.Gln368Arg	missense_variant	Exon 8 of 24	ENST00000611870.5	NP_207837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP4	ENST00000611870.5	c.1103A>G	p.Gln368Arg	missense_variant	Exon 8 of 24	1	NM_033401.5	ENSP00000479811.1
ENSG00000287694	ENST00000655556.1	n.1103A>G		non_coding_transcript_exon_variant	Exon 8 of 25			ENSP00000499374.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1103A>G (p.Q368R) alteration is located in exon 8 (coding exon 8) of the CNTNAP4 gene. This alteration results from a A to G substitution at nucleotide position 1103, causing the glutamine (Q) at amino acid position 368 to be replaced by an arginine (R). 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	0.069
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;.;.;.
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.78	T;D;T;D;D;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	.;.;.;.;D;D
REVEL	Benign	0.26
Sift	Benign	0.36	.;.;.;.;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.77	P;.;.;.;.;B
Vest4		0.62
MutPred		0.35		.;.;.;.;.;Loss of catalytic residue at M373 (P = 0.0304);
MVP		0.76
MPC		0.15
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.072
gMVP		0.35

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

hg19: chr16-76486436;