19-45213106-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001382422.1(EXOC3L2):c.2372G>A(p.Arg791Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,536,724 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R791W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 31)
  • Exomes 𝑓: 0.017 (238 hom.)
• Consequence: EXOC3L2 NM_001382422.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048166215).
• BP6: Variant 19-45213106-C-T is Benign according to our data. Variant chr19-45213106-C-T is described in ClinVar as [Benign]. Clinvar id is 1662737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0116 (1759/152146) while in subpopulation SAS AF= 0.0234 (113/4822). AF 95% confidence interval is 0.0199. There are 19 homozygotes in gnomad4. There are 880 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC3L2	NM_001382422.1	c.2372G>A	p.Arg791Gln	missense_variant	12/12	ENST00000413988.3
BLOC1S3	XR_007066811.1	n.1527-3570C>T		intron_variant, non_coding_transcript_variant
BLOC1S3	XR_007066813.1	n.1499-3570C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC3L2	ENST00000413988.3	c.2372G>A	p.Arg791Gln	missense_variant	12/12	5	NM_001382422.1	P1
MARK4	ENST00000587566.5	c.-276-45883C>T		intron_variant		5
BLOC1S3	ENST00000591569.1	n.283-3570C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1759 AN: 152028 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00721

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0143 AC: 2357 AN: 165328 Hom.: 29 AF XY: 0.0153 AC XY: 1383 AN XY: 90372

Gnomad AFR exome AF: 0.00306

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.000152

Gnomad SAS exome AF: 0.0235

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0167 AC: 23161 AN: 1384578 Hom.: 238 Cov.: 32 AF XY: 0.0171 AC XY: 11691 AN XY: 682520

Gnomad4 AFR exome AF: 0.00228

Gnomad4 AMR exome AF: 0.00386

Gnomad4 ASJ exome AF: 0.00515

Gnomad4 EAS exome AF: 0.000159

Gnomad4 SAS exome AF: 0.0265

Gnomad4 FIN exome AF: 0.0211

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0116 AC: 1759 AN: 152146 Hom.: 19 Cov.: 31 AF XY: 0.0118 AC XY: 880 AN XY: 74374

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.00720

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0173

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.0142 Hom.: 10

Bravo AF: 0.00980

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00301 AC: 13

ESP6500EA AF: 0.0127 AC: 108

ExAC AF: 0.0128 AC: 1540

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.64	T
REVEL	Benign	0.024
Polyphen		0.46	.;P
Vest4		0.082
MPC		0.14
ClinPred		0.049	T
GERP RS		1.3
Varity_R		0.056
gMVP		0.61

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: rs189063316; hg19: chr19-45716364; COSMIC: COSV52972217;