11-96391052-A-G

Position:

• chr11-96391052-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001261833.2(JRKL):​c.403A>G​(p.Ile135Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: JRKL NM_001261833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

Genes affected

JRKL (HGNC:6200): (JRK like) The function of this gene has not yet been defined, however, the encoded protein shares similarity with the human (41% identical) and mouse (34% identical) jerky gene products. This protein may act as a nuclear regulatory protein. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

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=0.37362432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JRKL	NM_001261833.2	c.403A>G	p.Ile135Val	missense_variant	2/2	ENST00000332349.5
JRKL	NM_003772.4	c.403A>G	p.Ile135Val	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JRKL	ENST00000332349.5	c.403A>G	p.Ile135Val	missense_variant	2/2	2	NM_001261833.2	P1
JRKL	ENST00000546177.1	n.85+979A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727236

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2023

The c.403A>G (p.I135V) alteration is located in exon 1 (coding exon 1) of the JRKL gene. This alteration results from a A to G substitution at nucleotide position 403, causing the isoleucine (I) at amino acid position 135 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.72	N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.26
Sift	Benign	0.15	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.68		Gain of MoRF binding (P = 0.1052);
MVP		0.50
ClinPred		0.81	D
GERP RS		4.6
Varity_R		0.078
gMVP		0.37

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: rs1378523836; hg19: chr11-96124216;