14-20429334-C-T

Variant names:

• chr14-20429334-C-T
• rs924978478
• NM_001365790.2:c.1909G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365790.2(KLHL33):​c.1909G>A​(p.Val637Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,399,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.680

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.387142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL33	NM_001365790.2	c.1909G>A	p.Val637Met	missense_variant	Exon 5 of 5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3	c.1117G>A	p.Val373Met	missense_variant	Exon 4 of 4		NP_001103467.2
KLHL33	XM_011536450.3	c.1909G>A	p.Val637Met	missense_variant	Exon 5 of 5		XP_011534752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL33	ENST00000636854.3	c.1909G>A	p.Val637Met	missense_variant	Exon 5 of 5	5	NM_001365790.2	ENSP00000490040.1
KLHL33	ENST00000344581.4	c.1117G>A	p.Val373Met	missense_variant	Exon 4 of 4	5		ENSP00000341549.4
KLHL33	ENST00000637228	c.*68G>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000489731.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000114 AC: 16 AN: 1399414 Hom.: 0 Cov.: 37 AF XY: 0.00000869 AC XY: 6 AN XY: 690208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000839

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	1.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.2	.;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.010	.;D
Polyphen		0.97	.;D
Vest4		0.39
MVP		0.088
ClinPred		0.61	D
GERP RS		-3.5
Varity_R		0.12
gMVP		0.45

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: rs924978478; hg19: chr14-20897493; COSMIC: COSV60727801;