chr14-44934323-G-T

Variant names:

• chr14-44934323-G-T
• rs749009458
• NM_017658.5:c.1135C>A

Variant summary

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

The NM_017658.5(KLHL28):​c.1135C>A​(p.Leu379Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,578 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: 0.0000096 (0 hom.)
• Consequence: KLHL28 NM_017658.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33

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 rank	MANE	Protein	UniProt
KLHL28	NM_017658.5	c.1135C>A	p.Leu379Ile	missense_variant	Exon 3 of 5	ENST00000396128.9	NP_060128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL28	ENST00000396128.9	c.1135C>A	p.Leu379Ile	missense_variant	Exon 3 of 5	1	NM_017658.5	ENSP00000379434.4
KLHL28	ENST00000355081.3	c.1177C>A	p.Leu393Ile	missense_variant	Exon 3 of 5	1		ENSP00000347193.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251340 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461578 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727100

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: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1135C>A (p.L379I) 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 1135, causing the leucine (L) at amino acid position 379 to be replaced by an isoleucine (I). 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	0.24
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;.
Vest4		0.51
MutPred		0.53		Gain of catalytic residue at L384 (P = 0);.;
MVP		0.92
MPC		1.5
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.34

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: rs749009458; hg19: chr14-45403526;