14-59498729-A-C

Variant names:

• chr14-59498729-A-C
• NM_016475.5:c.461A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016475.5(JKAMP):​c.461A>C​(p.Tyr154Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JKAMP NM_016475.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.09
• Publications: 0 publications found

Genes affected

JKAMP (HGNC:20184): (JNK1/MAPK8 associated membrane protein) Enables ubiquitin protein ligase binding activity. Involved in ubiquitin-dependent ERAD pathway. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

L3HYPDH (HGNC:20488): (trans-L-3-hydroxyproline dehydratase) The protein encoded by this gene is a dehydratase that converts trans-3-hydroxy-L-proline to delta(1)-pyrroline-2-carboxylate. This enzyme may function to degrade dietary proteins that contain trans-3-hydroxy-L-proline as well as other proteins such as collagen IV. The encoded protein can be converted to an epimerase by changing a threonine to a cysteine at a catalytic site. [provided by RefSeq, Sep 2016]

ENSG00000258782 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016475.5. 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
	JKAMP	NM_016475.5	MANE Select	c.461A>C	p.Tyr154Ser	missense splice_region	Exon 5 of 7	NP_057559.2
	JKAMP	NM_001284201.2		c.503A>C	p.Tyr168Ser	missense splice_region	Exon 5 of 7	NP_001271130.1	G3V2M4
	JKAMP	NM_001284202.2		c.485A>C	p.Tyr162Ser	missense splice_region	Exon 6 of 8	NP_001271131.1	Q9P055-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JKAMP	ENST00000616435.5	TSL:5 MANE Select	c.461A>C	p.Tyr154Ser	missense splice_region	Exon 5 of 7	ENSP00000479775.2	Q9P055-4
	JKAMP	ENST00000356057.9	TSL:1	c.485A>C	p.Tyr162Ser	missense splice_region	Exon 6 of 8	ENSP00000348351.5	Q9P055-5
	JKAMP	ENST00000425728.6	TSL:1	c.443A>C	p.Tyr148Ser	missense splice_region	Exon 5 of 7	ENSP00000389699.2	Q9P055-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00117 AC: 1522 AN: 1301918 Hom.: 0 Cov.: 18 AF XY: 0.00109 AC XY: 708 AN XY: 652250

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

African (AFR) AF: 0.000696 AC: 20 AN: 28744

American (AMR) AF: 0.00 AC: 0 AN: 34974

Ashkenazi Jewish (ASJ) AF: 0.000295 AC: 7 AN: 23734

East Asian (EAS) AF: 0.000263 AC: 10 AN: 37980

South Asian (SAS) AF: 0.000426 AC: 32 AN: 75036

European-Finnish (FIN) AF: 0.0000580 AC: 3 AN: 51706

Middle Eastern (MID) AF: 0.000559 AC: 3 AN: 5366

European-Non Finnish (NFE) AF: 0.00141 AC: 1399 AN: 989812

Other (OTH) AF: 0.000880 AC: 48 AN: 54566

⚠️ 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.: 32

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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.032	T
PhyloP100		9.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.55
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.89
Mutation Taster		=14/86	disease causing

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

Other links and lift over

hg19: chr14-59965447; COSMIC: COSV107201273; COSMIC: COSV107201273;