19-45213131-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001382422.1(EXOC3L2):c.2347A>G(p.Ser783Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,574,012 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (6 hom.)
• Consequence: EXOC3L2 NM_001382422.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.843

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038104653).
• BP6: Variant 19-45213131-T-C is Benign according to our data. Variant chr19-45213131-T-C is described in ClinVar as [Benign]. Clinvar id is 1572510.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC3L2	NM_001382422.1	c.2347A>G	p.Ser783Gly	missense_variant	12/12	ENST00000413988.3
BLOC1S3	XR_007066811.1	n.1527-3545T>C		intron_variant, non_coding_transcript_variant
BLOC1S3	XR_007066813.1	n.1499-3545T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC3L2	ENST00000413988.3	c.2347A>G	p.Ser783Gly	missense_variant	12/12	5	NM_001382422.1	P1
MARK4	ENST00000587566.5	c.-276-45858T>C		intron_variant		5
BLOC1S3	ENST00000591569.1	n.283-3545T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152054 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.000949 AC: 191 AN: 201264 Hom.: 2 AF XY: 0.000777 AC XY: 86 AN XY: 110694

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000570

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000663

Gnomad SAS exome AF: 0.0000768

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000761

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000388 AC: 552 AN: 1421840 Hom.: 6 Cov.: 31 AF XY: 0.000344 AC XY: 242 AN XY: 704476

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.000533

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0000608

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000174

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152172 Hom.: 1 Cov.: 31 AF XY: 0.00386 AC XY: 287 AN XY: 74406

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00444

ESP6500AA AF: 0.0125 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000866 AC: 3 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

Jul 17, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.5
Dann	Benign	0.78
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
REVEL	Benign	0.016
Polyphen		0.0	.;B
Vest4		0.072
MVP		0.068
MPC		0.11
ClinPred		0.00056	T
GERP RS		-2.4
Varity_R		0.039
gMVP		0.40

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: rs181444579; hg19: chr19-45716389;