10-30026673-A-G

Position:

• chr10-30026673-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020848.4(JCAD):​c.3475T>C​(p.Phe1159Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,140 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: JCAD NM_020848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

Genes affected

JCAD (HGNC:29283): (junctional cadherin 5 associated) This gene encodes an endothelial cell-to-cell junction protein. Naturally occurring mutations in this gene are associated with coronary artery disease, late onset alzheimer disease, and emphysema distribution. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JCAD	NM_020848.4	c.3475T>C	p.Phe1159Leu	missense_variant	3/4	ENST00000375377.2	NP_065899.1
JCAD	NM_001350022.2	c.3475T>C	p.Phe1159Leu	missense_variant	4/5		NP_001336951.1
JCAD	NM_001350001.2	c.3061T>C	p.Phe1021Leu	missense_variant	4/5		NP_001336930.1
JCAD	NM_001350021.2	c.3061T>C	p.Phe1021Leu	missense_variant	4/5		NP_001336950.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JCAD	ENST00000375377.2	c.3475T>C	p.Phe1159Leu	missense_variant	3/4	5	NM_020848.4	ENSP00000364526.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461140 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726860

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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

Dec 05, 2024

The c.3475T>C (p.F1159L) alteration is located in exon 3 (coding exon 2) of the KIAA1462 gene. This alteration results from a T to C substitution at nucleotide position 3475, causing the phenylalanine (F) at amino acid position 1159 to be replaced by a leucine (L). 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.0078	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.095	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.54		Loss of methylation at K1155 (P = 0.0923);
MVP		0.49
MPC		0.72
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.71
gMVP		0.21

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: rs1836812047; hg19: chr10-30315602;