rs346763

Variant names:

• chr19-45226017-G-A
• rs346763
• NM_001382422.1:c.1584-1104C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001382422.1(EXOC3L2):​c.1584-1104C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.099 in 152,130 control chromosomes in the GnomAD database, including 1,105 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.099 (1105 hom., cov: 31)
• Consequence: EXOC3L2 NM_001382422.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 5 publications found

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]

MARK4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC3L2	NM_001382422.1	c.1584-1104C>T		intron_variant	Intron 7 of 11	ENST00000413988.3	NP_001369351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC3L2	ENST00000413988.3	c.1584-1104C>T		intron_variant	Intron 7 of 11	5	NM_001382422.1	ENSP00000400713.2
MARK4	ENST00000587566.5	c.-276-32972G>A		intron_variant	Intron 1 of 6	5		ENSP00000465414.1

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15039 AN: 152012 Hom.: 1102 Cov.: 31

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0727

Gnomad FIN AF: 0.0983

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0750

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0990 AC: 15066 AN: 152130 Hom.: 1105 Cov.: 31 AF XY: 0.0994 AC XY: 7395 AN XY: 74374

African (AFR) AF: 0.203 AC: 8411 AN: 41480

American (AMR) AF: 0.0560 AC: 855 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3468

East Asian (EAS) AF: 0.103 AC: 534 AN: 5176

South Asian (SAS) AF: 0.0724 AC: 349 AN: 4822

European-Finnish (FIN) AF: 0.0983 AC: 1041 AN: 10588

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0511 AC: 3473 AN: 68010

Other (OTH) AF: 0.0809 AC: 171 AN: 2114

Alfa AF: 0.0712 Hom.: 294

Bravo AF: 0.0998

Asia WGS AF: 0.115 AC: 399 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.59
DANN	Benign	0.90
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs346763; hg19: chr19-45729275;