14-20435747-C-T

Variant names:

• chr14-20435747-C-T
• rs8017603
• NM_001365790.2:c.65G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001365790.2(KLHL33):​c.65G>A​(p.Arg22Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,233,928 control chromosomes in the GnomAD database, including 151,778 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 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: 𝑓 0.48 (17441 hom., cov: 31)
  • Exomes 𝑓: 0.50 (134337 hom.)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.212
• Publications: 17 publications found

Genes affected

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

ENSG00000291038 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8199635E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365790.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL33	NM_001365790.2	MANE Select	c.65G>A	p.Arg22Lys	missense	Exon 2 of 5	NP_001352719.1	A0A1B0GUB7
	KLHL33	NM_001109997.3		c.-328G>A		5_prime_UTR	Exon 1 of 4	NP_001103467.2	A6NCF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL33	ENST00000636854.3	TSL:5 MANE Select	c.65G>A	p.Arg22Lys	missense	Exon 2 of 5	ENSP00000490040.1	A0A1B0GUB7
	KLHL33	ENST00000637228.1	TSL:5	c.65G>A	p.Arg22Lys	missense	Exon 1 of 4	ENSP00000489731.1	A0A1B0GTK0
	ENSG00000291038	ENST00000800199.1		n.213-2113C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72392 AN: 151680 Hom.: 17406 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.497 AC: 538285 AN: 1082126 Hom.: 134337 Cov.: 39 AF XY: 0.498 AC XY: 254443 AN XY: 510974

African (AFR) AF: 0.423 AC: 9755 AN: 23042

American (AMR) AF: 0.454 AC: 3831 AN: 8430

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 7255 AN: 14396

East Asian (EAS) AF: 0.377 AC: 9990 AN: 26526

South Asian (SAS) AF: 0.542 AC: 10621 AN: 19590

European-Finnish (FIN) AF: 0.535 AC: 11546 AN: 21562

Middle Eastern (MID) AF: 0.610 AC: 2772 AN: 4546

European-Non Finnish (NFE) AF: 0.501 AC: 460827 AN: 920162

Other (OTH) AF: 0.494 AC: 21688 AN: 43872

GnomAD4 genome AF: 0.477 AC: 72484 AN: 151802 Hom.: 17441 Cov.: 31 AF XY: 0.480 AC XY: 35625 AN XY: 74168

African (AFR) AF: 0.435 AC: 17999 AN: 41394

American (AMR) AF: 0.452 AC: 6900 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1696 AN: 3472

East Asian (EAS) AF: 0.371 AC: 1893 AN: 5108

South Asian (SAS) AF: 0.528 AC: 2537 AN: 4808

European-Finnish (FIN) AF: 0.554 AC: 5845 AN: 10554

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33837 AN: 67878

Other (OTH) AF: 0.491 AC: 1036 AN: 2112

Alfa AF: 0.489 Hom.: 76980

Bravo AF: 0.467

TwinsUK AF: 0.512 AC: 1900

ALSPAC AF: 0.502 AC: 1934

Asia WGS AF: 0.457 AC: 1590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.4
DANN	Benign	0.83
DEOGEN2	Benign	0.0030	T
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.00068	T
PhyloP100		0.21
GERP RS		4.3
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs8017603; hg19: chr14-20903906; COSMIC: COSV60726366; COSMIC: COSV60726366;