14-44934370-G-T

Position:

• chr14-44934370-G-T

Variant summary

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

The ENST00000396128.9(KLHL28):​c.1088C>A​(p.Thr363Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHL28 ENST00000396128.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

Genes affected

KLHL28 (HGNC:19741): (kelch like family member 28)

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
KLHL28	NM_017658.5	c.1088C>A	p.Thr363Lys	missense_variant	3/5	ENST00000396128.9	NP_060128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL28	ENST00000396128.9	c.1088C>A	p.Thr363Lys	missense_variant	3/5	1	NM_017658.5	ENSP00000379434.4
KLHL28	ENST00000355081.3	c.1130C>A	p.Thr377Lys	missense_variant	3/5	1		ENSP00000347193.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251322 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 24, 2024

The c.1088C>A (p.T363K) alteration is located in exon 3 (coding exon 2) of the KLHL28 gene. This alteration results from a C to A substitution at nucleotide position 1088, causing the threonine (T) at amino acid position 363 to be replaced by a lysine (K). 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	0.21
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	0.077
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.57	T;T
Polyphen		0.012	B;.
Vest4		0.59
MutPred		0.56		Gain of catalytic residue at W359 (P = 0);.;
MVP		0.77
MPC		0.72
ClinPred		0.59	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.53

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: rs1368023859; hg19: chr14-45403573; COSMIC: COSV100753075;