Genetic Variant EXOC3L4:p.Arg77Trp (chr14-103100448-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001077594.2(EXOC3L4):c.229C>T(p.Arg77Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,946 control chromosomes in the GnomAD database, including 46,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.20 ( 3495 hom., cov: 33)

Exomes 𝑓: 0.24 ( 42629 hom. )

Consequence

EXOC3L4
NM_001077594.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.470

Publications

52 publications found

Variant links:

Genes affected

EXOC3L4 (HGNC:20120): (exocyst complex component 3 like 4) Predicted to enable SNARE binding activity. Predicted to be involved in exocyst localization and exocytosis. Predicted to be part of exocyst. [provided by Alliance of Genome Resources, Apr 2022]

EXOC3L4 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=0.0054156184).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC3L4	NM_001077594.2 link	c.229C>T	p.Arg77Trp	missense_variant	Exon 2 of 12	ENST00000688303.1	NP_001071062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EXOC3L4	ENST00000688303.1 link	c.229C>T	p.Arg77Trp	missense_variant	Exon 2 of 12		NM_001077594.2	ENSP00000509130.1
EXOC3L4	ENST00000380069.7 link	c.229C>T	p.Arg77Trp	missense_variant	Exon 1 of 11	1		ENSP00000369409.3
EXOC3L4	ENST00000687959.1 link	c.229C>T	p.Arg77Trp	missense_variant	Exon 3 of 13			ENSP00000508483.1
EXOC3L4	ENST00000559116.1 link	c.121C>T	p.Arg41Trp	missense_variant	Exon 1 of 3	5		ENSP00000454163.1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30638

AN:

152136

Hom.:

3488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.360

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.249

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.241

Gnomad OTH

AF:

0.228

GnomAD2 exomes

AF:

0.224

AC:

55862

AN:

248846

AF XY:

0.231

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.252

Gnomad FIN exome

AF:

0.221

Gnomad NFE exome

AF:

0.241

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.239

AC:

349792

AN:

1460692

Hom.:

42629

Cov.:

AF XY:

0.241

AC XY:

175257

AN XY:

726622

show subpopulations

African (AFR)

AF:

0.107

AC:

3583

AN:

33478

American (AMR)

AF:

0.167

AC:

7452

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

6567

AN:

26120

East Asian (EAS)

AF:

0.243

AC:

9631

AN:

39690

South Asian (SAS)

AF:

0.264

AC:

22728

AN:

86150

European-Finnish (FIN)

AF:

0.226

AC:

11928

AN:

52808

Middle Eastern (MID)

AF:

0.213

AC:

1227

AN:

5768

European-Non Finnish (NFE)

AF:

0.245

AC:

272232

AN:

1111672

Other (OTH)

AF:

0.239

AC:

14444

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17755

35510

53266

71021

88776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9234

18468

27702

36936

46170

<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:

0.201

AC:

30655

AN:

152254

Hom.:

3495

Cov.:

AF XY:

0.200

AC XY:

14918

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.112

AC:

4649

AN:

41564

American (AMR)

AF:

0.190

AC:

2908

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

865

AN:

3472

East Asian (EAS)

AF:

0.253

AC:

1310

AN:

5178

South Asian (SAS)

AF:

0.270

AC:

1304

AN:

4828

European-Finnish (FIN)

AF:

0.221

AC:

2343

AN:

10600

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.241

AC:

16399

AN:

67992

Other (OTH)

AF:

0.231

AC:

489

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1257

2514

3772

5029

6286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<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:

0.234

Hom.:

18190

Bravo

AF:

0.196

TwinsUK

AF:

0.249

AC:

925

ALSPAC

AF:

0.247

AC:

951

ESP6500AA

AF:

0.118

AC:

519

ESP6500EA

AF:

0.244

AC:

2098

ExAC

AF:

0.226

AC:

27453

Asia WGS

AF:

0.267

AC:

930

AN:

3478

EpiCase

AF:

0.246

EpiControl

AF:

0.249

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.097

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

PhyloP100

-0.47

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.064

Sift

Uncertain

0.027

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.081

MPC

0.24

ClinPred

0.058

GERP RS

-6.1

PromoterAI

-0.046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.24

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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