Genetic Variant NM_033401.5:c.3465T>G (chr16-76553305-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033401.5(CNTNAP4):c.3465T>G(p.Asp1155Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,604,446 control chromosomes in the GnomAD database, including 72,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 6851 hom., cov: 33)

Exomes 𝑓: 0.30 ( 65260 hom. )

Consequence

CNTNAP4
NM_033401.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0640

Publications

25 publications found

Variant links:

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]

CNTNAP4 links:

ENSG00000287694 (HGNC:):

ENSG00000287694 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055819154).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP4	NM_033401.5 link	c.3465T>G	p.Asp1155Glu	missense_variant	Exon 22 of 24	ENST00000611870.5	NP_207837.2	Q9C0A0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP4	ENST00000611870.5 link	c.3465T>G	p.Asp1155Glu	missense_variant	Exon 22 of 24	1	NM_033401.5	ENSP00000479811.1		Q9C0A0-1
ENSG00000287694	ENST00000655556.1 link	n.3465T>G		non_coding_transcript_exon_variant	Exon 22 of 25			ENSP00000499374.1		A0A590UJB1

Frequencies

GnomAD3 genomes

AF:

0.298

AC:

45326

AN:

152018

Hom.:

6833

Cov.:

show subpopulations

Gnomad AFR

AF:

0.348

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.279

Gnomad SAS

AF:

0.354

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.185

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.247

GnomAD2 exomes

AF:

0.286

AC:

70410

AN:

245814

AF XY:

0.289

show subpopulations

Gnomad AFR exome

AF:

0.345

Gnomad AMR exome

AF:

0.216

Gnomad ASJ exome

AF:

0.243

Gnomad EAS exome

AF:

0.285

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.290

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.297

AC:

430953

AN:

1452310

Hom.:

65260

Cov.:

AF XY:

0.298

AC XY:

214782

AN XY:

721484

show subpopulations

African (AFR)

AF:

0.343

AC:

11394

AN:

33260

American (AMR)

AF:

0.215

AC:

9564

AN:

44444

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6402

AN:

26048

East Asian (EAS)

AF:

0.291

AC:

11498

AN:

39478

South Asian (SAS)

AF:

0.359

AC:

30817

AN:

85826

European-Finnish (FIN)

AF:

0.262

AC:

13950

AN:

53300

Middle Eastern (MID)

AF:

0.179

AC:

1027

AN:

5736

European-Non Finnish (NFE)

AF:

0.298

AC:

328915

AN:

1104260

Other (OTH)

AF:

0.290

AC:

17386

AN:

59958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

13023

26046

39069

52092

65115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11002

22004

33006

44008

55010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.298

AC:

45376

AN:

152136

Hom.:

6851

Cov.:

AF XY:

0.296

AC XY:

22032

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.347

AC:

14425

AN:

41514

American (AMR)

AF:

0.234

AC:

3575

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

795

AN:

3472

East Asian (EAS)

AF:

0.279

AC:

1443

AN:

5164

South Asian (SAS)

AF:

0.353

AC:

1704

AN:

4826

European-Finnish (FIN)

AF:

0.260

AC:

2756

AN:

10580

Middle Eastern (MID)

AF:

0.185

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.293

AC:

19885

AN:

67966

Other (OTH)

AF:

0.255

AC:

539

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1640

3280

4921

6561

8201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.287

Hom.:

31778

Bravo

AF:

0.294

TwinsUK

AF:

0.301

AC:

1116

ALSPAC

AF:

0.294

AC:

1133

ESP6500AA

AF:

0.334

AC:

1309

ESP6500EA

AF:

0.279

AC:

2328

ExAC

AF:

0.292

AC:

35340

Asia WGS

AF:

0.370

AC:

1287

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.2

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.062

T;T;T;.;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.064

T;T;T;T;T;T

MetaRNN

Benign

0.0056

T;T;T;T;T;T

MetaSVM

Benign

-0.98

PhyloP100

-0.064

PrimateAI

Benign

0.46

PROVEAN

Benign

1.0

.;.;.;.;N;N

REVEL

Benign

0.036

Sift

Benign

1.0

.;.;.;.;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;B

Vest4

0.047

MutPred

0.30

.;.;.;.;.;Gain of disorder (P = 0.1807);

MPC

0.021

ClinPred

0.00062

GERP RS

3.3

Varity_R

0.043

gMVP

0.16

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over