14-20429040-C-G

Variant names:

• chr14-20429040-C-G
• rs891147302
• NM_001365790.2:c.2203G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001365790.2(KLHL33):​c.2203G>C​(p.Gly735Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94

Genes affected

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL33	NM_001365790.2	c.2203G>C	p.Gly735Arg	missense_variant	Exon 5 of 5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3	c.1411G>C	p.Gly471Arg	missense_variant	Exon 4 of 4		NP_001103467.2
KLHL33	XM_011536450.3	c.2203G>C	p.Gly735Arg	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.2203G>C	p.Gly735Arg	missense_variant	Exon 5 of 5	5	NM_001365790.2	ENSP00000490040.1
KLHL33	ENST00000344581.4	c.1411G>C	p.Gly471Arg	missense_variant	Exon 4 of 4	5		ENSP00000341549.4
KLHL33	ENST00000637228	c.*362G>C		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000489731.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.8	.;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	.;D
Vest4		0.92
MutPred		0.94		.;Gain of methylation at G471 (P = 0.0722);
MVP		0.49
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.89

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: rs891147302; hg19: chr14-20897199;