chr4-6062442-T-C

Variant names:

• chr4-6062442-T-C
• rs1135401781
• NM_001099433.2:c.1432-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001099433.2(JAKMIP1):​c.1432-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAKMIP1 NM_001099433.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59
• Publications: 1 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.051682692 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of 39, new splice context is: ctgacctgcgcttctgccAGctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099433.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAKMIP1	NM_001099433.2	MANE Select	c.1432-2A>G		splice_acceptor intron	N/A	NP_001092903.1
	JAKMIP1	NM_001306133.2		c.1432-2A>G		splice_acceptor intron	N/A	NP_001293062.1
	JAKMIP1	NM_144720.4		c.1432-2A>G		splice_acceptor intron	N/A	NP_653321.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAKMIP1	ENST00000409021.9	TSL:1 MANE Select	c.1432-2A>G		splice_acceptor intron	N/A	ENSP00000386711.3
	JAKMIP1	ENST00000409371.8	TSL:1	c.877-2A>G		splice_acceptor intron	N/A	ENSP00000387042.3
	JAKMIP1	ENST00000282924.9	TSL:1	c.1432-2A>G		splice_acceptor intron	N/A	ENSP00000282924.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	33
DANN	Benign	0.93
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
GERP RS		4.7
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.84		Position offset: -1
DS_AL_spliceai		1.0		Position offset: -2

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

Other links and lift over

dbSNP: rs1135401781; hg19: chr4-6064169;