14-20435747-C-T

Position:

• chr14-20435747-C-T

Variant summary

Our verdict is Benign. Variant got -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. 5/6 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

Genes affected

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

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL33	NM_001365790.2	c.65G>A	p.Arg22Lys	missense_variant	2/5	ENST00000636854.3	NP_001352719.1
KLHL33	XM_011536450.3	c.65G>A	p.Arg22Lys	missense_variant	2/5		XP_011534752.1
KLHL33	NM_001109997.3	c.-328G>A		5_prime_UTR_variant	1/4		NP_001103467.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL33	ENST00000636854.3	c.65G>A	p.Arg22Lys	missense_variant	2/5	5	NM_001365790.2	ENSP00000490040.1
KLHL33	ENST00000637228.1	c.65G>A	p.Arg22Lys	missense_variant	1/4	5		ENSP00000489731.1

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

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.504

Gnomad4 EAS exome AF: 0.377

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.535

Gnomad4 NFE exome AF: 0.501

Gnomad4 OTH exome AF: 0.494

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

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.528

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.498

Gnomad4 OTH AF: 0.491

Alfa AF: 0.491 Hom.: 37557

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 v4.3

Name	Calibrated prediction	Score	Prediction
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;T
MetaRNN	Benign	0.00068	T;T
GERP RS		4.3

Splicing

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

Publications

LitVar

Other links and lift over

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