chr14-20429175-G-T

Position:

• chr14-20429175-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365790.2(KLHL33):​c.2068C>A​(p.Leu690Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,399,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00800

Genes affected

KLHL33 (HGNC:31952): (kelch like family member 33)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13615471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL33	NM_001365790.2	c.2068C>A	p.Leu690Met	missense_variant	5/5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3	c.1276C>A	p.Leu426Met	missense_variant	4/4		NP_001103467.2
KLHL33	XM_011536450.3	c.2068C>A	p.Leu690Met	missense_variant	5/5		XP_011534752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL33	ENST00000636854.3	c.2068C>A	p.Leu690Met	missense_variant	5/5	5	NM_001365790.2	ENSP00000490040.1
KLHL33	ENST00000344581.4	c.1276C>A	p.Leu426Met	missense_variant	4/4	5		ENSP00000341549.4
KLHL33	ENST00000637228	c.*227C>A		3_prime_UTR_variant	4/4	5		ENSP00000489731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000171 AC: 24 AN: 1399426 Hom.: 0 Cov.: 37 AF XY: 0.0000203 AC XY: 14 AN XY: 690224

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: 0.0000167

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

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

Jul 12, 2022

The c.1276C>A (p.L426M) alteration is located in exon 4 (coding exon 3) of the KLHL33 gene. This alteration results from a C to A substitution at nucleotide position 1276, causing the leucine (L) at amino acid position 426 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.4
DANN	Benign	0.95
DEOGEN2	Benign	0.0095	T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.17	.;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.040	.;N
REVEL	Benign	0.13
Sift	Benign	0.10	.;T
Sift4G	Benign	0.089	.;T
Polyphen		0.35	.;B
Vest4		0.32
MutPred		0.56		.;Gain of phosphorylation at T429 (P = 0.1429);
MVP		0.030
ClinPred		0.076	T
GERP RS		0.28
Varity_R		0.065
gMVP		0.22

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: rs866215214; hg19: chr14-20897334;