16-1706620-A-G

Position:

• chr16-1706620-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.13

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAPK8IP3. . Gene score misZ 2.8844 (greater than the threshold 3.09). Trascript score misZ 3.4182 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with or without variable brain abnormalities; NEDBA.
• 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 id is 916590.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK8IP3	NM_001318852.2	c.281A>G	p.Tyr94Cys	missense_variant	1/32	ENST00000610761.2	NP_001305781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK8IP3	ENST00000610761.2	c.281A>G	p.Tyr94Cys	missense_variant	1/32	1	NM_001318852.2	ENSP00000481780	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1436298 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with or without variable brain abnormalities; NEDBA Pathogenic:1

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D;D;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MutPred		0.75		Loss of phosphorylation at Y94 (P = 0.1636);Loss of phosphorylation at Y94 (P = 0.1636);Loss of phosphorylation at Y94 (P = 0.1636);
MVP		0.68
MPC		1.9
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.87
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs2037399601; hg19: chr16-1756621;