4-6062313-C-T

Position:

chr4-6062313-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001099433.2(JAKMIP1):c.1559G>A(p.Arg520Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

JAKMIP1
NM_001099433.2 missense, splice_region

Scores

Splicing: ADA: 0.8598

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.95

Variant links:

Genes affected

JAKMIP1 (HGNC:26460): (janus kinase and microtubule interacting protein 1) Enables GABA receptor binding activity and RNA binding activity. Involved in cognition. Is extrinsic component of membrane. Part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

JAKMIP1 links:

C4orf50 (HGNC:33766): (chromosome 4 open reading frame 50)

C4orf50 links:

JAKMIP1 (HGNC:):

JAKMIP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2661846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAKMIP1	NM_001099433.2 linkuse as main transcript	c.1559G>A	p.Arg520Gln	missense_variant, splice_region_variant	10/21	ENST00000409021.9	NP_001092903.1	Q96N16-2
JAKMIP1	NM_001306133.2 linkuse as main transcript	c.1559G>A	p.Arg520Gln	missense_variant, splice_region_variant	10/13		NP_001293062.1	Q96N16-1B3KWB6
JAKMIP1	NM_144720.4 linkuse as main transcript	c.1559G>A	p.Arg520Gln	missense_variant, splice_region_variant	10/13		NP_653321.1	Q96N16-1
JAKMIP1	NM_001306134.2 linkuse as main transcript	c.1064G>A	p.Arg355Gln	missense_variant, splice_region_variant	9/12		NP_001293063.1	Q96N16-7B3KWB6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAKMIP1	ENST00000409021.9 linkuse as main transcript	c.1559G>A	p.Arg520Gln	missense_variant, splice_region_variant	10/21	1	NM_001099433.2	ENSP00000386711.3		Q96N16-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249640

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1459920

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726332

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.1559G>A (p.R520Q) alteration is located in exon 10 (coding exon 9) of the JAKMIP1 gene. This alteration results from a G to A substitution at nucleotide position 1559, causing the arginine (R) at amino acid position 520 to be replaced by a glutamine (Q). 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

0.25

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.042

T;.;.;T;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.7

.;L;.;L;L;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.4

.;N;N;N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.017

.;D;D;D;D;D

Sift4G

Uncertain

0.016

.;D;D;D;D;D

Polyphen

0.98, 1.0

.;D;D;D;D;.

Vest4

0.58, 0.55, 0.56, 0.59

MutPred

0.16

.;Loss of phosphorylation at T521 (P = 0.1515);.;Loss of phosphorylation at T521 (P = 0.1515);Loss of phosphorylation at T521 (P = 0.1515);.;

MVP

0.31

MPC

1.8

ClinPred

0.51

GERP RS

4.8

Varity_R

0.37

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.86

dbscSNV1_RF

Benign

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over