19-45213213-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001382422.1(EXOC3L2):c.2265C>A(p.Asp755Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,611,642 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: EXOC3L2 NM_001382422.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09

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]

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010788709).
• BP6: Variant 19-45213213-G-T is Benign according to our data. Variant chr19-45213213-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2056575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC3L2	NM_001382422.1	c.2265C>A	p.Asp755Glu	missense_variant	12/12	ENST00000413988.3
BLOC1S3	XR_007066811.1	n.1527-3463G>T		intron_variant, non_coding_transcript_variant
BLOC1S3	XR_007066813.1	n.1499-3463G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC3L2	ENST00000413988.3	c.2265C>A	p.Asp755Glu	missense_variant	12/12	5	NM_001382422.1	P1
MARK4	ENST00000587566.5	c.-276-45776G>T		intron_variant		5
BLOC1S3	ENST00000591569.1	n.283-3463G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 152 AN: 152112 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00101 AC: 249 AN: 245900 Hom.: 1 AF XY: 0.00100 AC XY: 134 AN XY: 133382

Gnomad AFR exome AF: 0.000314

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000694

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00116 AC: 1686 AN: 1459412 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 773 AN XY: 725996

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000744

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.000913

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152230 Hom.: 1 Cov.: 31 AF XY: 0.00110 AC XY: 82 AN XY: 74432

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00119

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000873 AC: 106

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EXOC3L2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	16
Dann	Uncertain	1.0
Eigen	Benign	-0.024
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Pathogenic	0.84	D
REVEL	Benign	0.094
Polyphen		0.91	.;P
Vest4		0.14
MutPred		0.40		.;Gain of sheet (P = 0.0149);
MVP		0.043
MPC		0.29
ClinPred		0.020	T
GERP RS		4.5
Varity_R		0.23
gMVP		0.46

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

Other links and lift over

dbSNP: rs111862689; hg19: chr19-45716471;