rs770703007

Positions:

• chr16-1706450-C-G
• chr16-1706450-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001318852.2(MAPK8IP3):​c.111C>G​(p.Tyr37Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPK8IP3 NM_001318852.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.88

Genes affected

MAPK8IP3 (HGNC:6884): (mitogen-activated protein kinase 8 interacting protein 3) The protein encoded by this gene shares similarity with the product of Drosophila syd gene, required for the functional interaction of kinesin I with axonal cargo. Studies of the similar gene in mouse suggested that this protein may interact with, and regulate the activity of numerous protein kinases of the JNK signaling pathway, and thus function as a scaffold protein in neuronal cells. The C. elegans counterpart of this gene is found to regulate synaptic vesicle transport possibly by integrating JNK signaling and kinesin-1 transport. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-1706450-C-G is Pathogenic according to our data. Variant chr16-1706450-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 598741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK8IP3	NM_001318852.2	c.111C>G	p.Tyr37Ter	stop_gained	1/32	ENST00000610761.2	NP_001305781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK8IP3	ENST00000610761.2	c.111C>G	p.Tyr37Ter	stop_gained	1/32	1	NM_001318852.2	ENSP00000481780	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with or without variable brain abnormalities; NEDBA Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 02, 2019	This variant is interpreted as a Likely pathogenic for Neurodevelopmental disorder with or without variable brain abnormalities, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PVS1-Strong. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 07, 2019	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 23, 2019	- -

MAPK8IP3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Oct 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.80
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs770703007; hg19: chr16-1756451;