19-45213088-C-T

Position:

chr19-45213088-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001382422.1(EXOC3L2):c.2390G>A(p.Arg797Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,511,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

EXOC3L2
NM_001382422.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Variant links:

Genes affected

EXOC3L2 (HGNC:30162): (exocyst complex component 3 like 2) The protein encoded by this gene is upregulated by vascular endothelial growth factor A and interacts with exocyst complex component 4. The encoded protein may be part of an exocyst complex that plays a role in cell membrane dynamics. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, May 2017]

EXOC3L2 links:

MARK4 (HGNC:13538): (microtubule affinity regulating kinase 4) This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer's disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

MARK4 links:

BLOC1S3 (HGNC:20914): (biogenesis of lysosomal organelles complex 1 subunit 3) This gene encodes a protein that is a component of the BLOC1 multi-subunit protein complex. This complex is necessary for the biogenesis of specialized organelles of the endosomal-lysosomal system, including platelet dense granules and melanosomes. Mutations in this gene cause Hermansky-Pudlak syndrome 8, a disease characterized by lysosomal storage defects, bleeding due to platelet storage pool deficiency, and oculocutaneous albinism. [provided by RefSeq, Jul 2008]

BLOC1S3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020495474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EXOC3L2	NM_001382422.1 linkuse as main transcript	c.2390G>A	p.Arg797Gln	missense_variant	12/12	ENST00000413988.3
BLOC1S3	XR_007066811.1 linkuse as main transcript	n.1527-3588C>T		intron_variant, non_coding_transcript_variant
BLOC1S3	XR_007066813.1 linkuse as main transcript	n.1499-3588C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EXOC3L2	ENST00000413988.3 linkuse as main transcript	c.2390G>A	p.Arg797Gln	missense_variant	12/12	5	NM_001382422.1	P1
MARK4	ENST00000587566.5 linkuse as main transcript	c.-276-45901C>T		intron_variant		5
BLOC1S3	ENST00000591569.1 linkuse as main transcript	n.283-3588C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000750

AC:

114

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000333

AC:

AN:

141080

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

75910

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.000706

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000213

AC:

289

AN:

1359036

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

135

AN XY:

666906

show subpopulations

Gnomad4 AFR exome

AF:

0.00113

Gnomad4 AMR exome

AF:

0.000585

Gnomad4 ASJ exome

AF:

0.0000483

Gnomad4 EAS exome

AF:

0.000267

Gnomad4 SAS exome

AF:

0.0000286

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.000445

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152200

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00188

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000437

Hom.:

Bravo

AF:

0.000812

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00117

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.000235

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 404 of the EXOC3L2 protein (p.Arg404Gln). This variant is present in population databases (rs199587359, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with EXOC3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1503657). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.67

REVEL

Benign

0.13

Polyphen

0.98

.;D

Vest4

0.13

MVP

0.043

MPC

0.14

ClinPred

0.047

GERP RS

3.5

Varity_R

0.074

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over