chr4-6056726-T-C

Variant names:

• chr4-6056726-T-C
• NM_001099433.2:c.1678A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099433.2(JAKMIP1):​c.1678A>G​(p.Ile560Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JAKMIP1 NM_001099433.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.786
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12512639).

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.1678A>G	p.Ile560Val	missense	Exon 12 of 21	NP_001092903.1	Q96N16-2
	JAKMIP1	NM_001306133.2		c.1678A>G	p.Ile560Val	missense	Exon 12 of 13	NP_001293062.1	Q96N16-1
	JAKMIP1	NM_144720.4		c.1678A>G	p.Ile560Val	missense	Exon 12 of 13	NP_653321.1	Q96N16-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAKMIP1	ENST00000409021.9	TSL:1 MANE Select	c.1678A>G	p.Ile560Val	missense	Exon 12 of 21	ENSP00000386711.3	Q96N16-2
	JAKMIP1	ENST00000409371.8	TSL:1	c.1123A>G	p.Ile375Val	missense	Exon 10 of 19	ENSP00000387042.3	Q96N16-5
	JAKMIP1	ENST00000282924.9	TSL:1	c.1678A>G	p.Ile560Val	missense	Exon 12 of 13	ENSP00000282924.5	Q96N16-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461392 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727048

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.79
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.032
Sift	Benign	0.090	T
Sift4G	Benign	0.38	T
Polyphen		0.048	B
Vest4		0.12
MutPred		0.18		Gain of ubiquitination at K556 (P = 0.0843)
MVP		0.38
MPC		0.55
ClinPred		0.10	T
GERP RS		3.8
Varity_R		0.046
gMVP		0.056
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr4-6058453;