chr16-1706363-G-T

Position:

• chr16-1706363-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001318852.2(MAPK8IP3):​c.24G>T​(p.Glu8Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAPK8IP3 NM_001318852.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.773

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_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04542139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8IP3	NM_001318852.2	c.24G>T	p.Glu8Asp	missense_variant	1/32	ENST00000610761.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8IP3	ENST00000610761.2	c.24G>T	p.Glu8Asp	missense_variant	1/32	1	NM_001318852.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000440 AC: 1 AN: 227404 Hom.: 0 AF XY: 0.00000804 AC XY: 1 AN XY: 124402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449594 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000230

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2019

The alteration results in an amino acid change:_x000D_ _x000D_ The c.24G>T (p.E8D) alteration is located in coding exon 1 of the MAPK8IP3 gene. This alteration results from a G to T substitution at nucleotide position 24, causing the glutamic acid (E) at amino acid position 8 to be replaced by an aspartic acid (D). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.24G>T alteration was observed in 0.00044% (1/227404) of total alleles studied. The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.E8 amino acid is conserved through mammals, but aspartic acid (D) is the reference amino acid in non-mammalian vertebrates. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.E8D alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	20
DANN	Benign	0.65
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;.;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.020	N;N;.
REVEL	Benign	0.013
Sift	Benign	0.16	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.13
MutPred		0.33		Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);
MVP		0.20
MPC		0.59
ClinPred		0.087	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.55

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: rs946554586; hg19: chr16-1756364;