Genetic Variant MAPK8IP3:p.Tyr94Cys (chr16-1706620-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_001318852.2(MAPK8IP3):c.281A>G(p.Tyr94Cys) variant causes a missense 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAPK8IP3
NM_001318852.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.13

Publications

0 publications found

Variant links:

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]

MAPK8IP3 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with or without variable brain abnormalities; NEDBA
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

MAPK8IP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 16-1706620-A-G is Pathogenic according to our data. Variant chr16-1706620-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 916590.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318852.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPK8IP3	NM_001318852.2	MANE Select	c.281A>G	p.Tyr94Cys	missense	Exon 1 of 32	NP_001305781.1	A0A087WYG2
MAPK8IP3	NM_015133.5		c.281A>G	p.Tyr94Cys	missense	Exon 1 of 32	NP_055948.2	Q9UPT6-1
MAPK8IP3	NM_001040439.2		c.281A>G	p.Tyr94Cys	missense	Exon 1 of 31	NP_001035529.1	E9PFH7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPK8IP3	ENST00000610761.2	TSL:1 MANE Select	c.281A>G	p.Tyr94Cys	missense	Exon 1 of 32	ENSP00000481780.1	A0A087WYG2
MAPK8IP3	ENST00000250894.8	TSL:1	c.281A>G	p.Tyr94Cys	missense	Exon 1 of 32	ENSP00000250894.4	Q9UPT6-1
MAPK8IP3	ENST00000561765.1	TSL:1	n.242A>G		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1436298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712626

African (AFR)

AF:

0.00

AC:

AN:

32790

American (AMR)

AF:

0.00

AC:

AN:

40466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25650

East Asian (EAS)

AF:

0.00

AC:

AN:

38098

South Asian (SAS)

AF:

0.00

AC:

AN:

83228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099920

Other (OTH)

AF:

0.00

AC:

AN:

59428

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with or without variable brain abnormalities; NEDBA (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.0

PhyloP100

7.1

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MutPred

0.75

Loss of phosphorylation at Y94 (P = 0.1636)

MVP

0.68

MPC

1.9

ClinPred

1.0

GERP RS

3.7

PromoterAI

-0.097

Neutral

(source)

Varity_R

0.87

gMVP

0.98

Mutation Taster

=64/36

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over