14-20429358-C-T

Position:

• chr14-20429358-C-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.1885G>A​(p.Ala629Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 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)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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=0.17380786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL33	NM_001365790.2	c.1885G>A	p.Ala629Thr	missense_variant	5/5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3	c.1093G>A	p.Ala365Thr	missense_variant	4/4		NP_001103467.2
KLHL33	XM_011536450.3	c.1885G>A	p.Ala629Thr	missense_variant	5/5		XP_011534752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL33	ENST00000636854.3	c.1885G>A	p.Ala629Thr	missense_variant	5/5	5	NM_001365790.2	ENSP00000490040.1
KLHL33	ENST00000344581.4	c.1093G>A	p.Ala365Thr	missense_variant	4/4	5		ENSP00000341549.4
KLHL33	ENST00000637228	c.*44G>A		3_prime_UTR_variant	4/4	5		ENSP00000489731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

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

Jan 26, 2022

The c.1093G>A (p.A365T) alteration is located in exon 4 (coding exon 3) of the KLHL33 gene. This alteration results from a G to A substitution at nucleotide position 1093, causing the alanine (A) at amino acid position 365 to be replaced by a threonine (T). 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	0.086
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.0077	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.2	.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.34	.;N
REVEL	Benign	0.27
Sift	Benign	1.0	.;T
Sift4G	Benign	0.90	.;T
Polyphen		0.029	.;B
Vest4		0.19
MutPred		0.61		.;Gain of catalytic residue at A365 (P = 0.1578);
MVP		0.23
ClinPred		0.31	T
GERP RS		3.6
Varity_R		0.028
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-20897517;