rs7145318

chr14-20428905-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.2338G>A(p.Ala780Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 1,551,436 control chromosomes in the GnomAD database, including 272,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.62 (29766 hom., cov: 34)
  • Exomes 𝑓: 0.59 (242308 hom.)
• Consequence: KLHL33 NM_001365790.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.877

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=1.5052747E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL33	NM_001365790.2	c.2338G>A	p.Ala780Thr	missense_variant	5/5	ENST00000636854.3
KLHL33	NM_001109997.3	c.1546G>A	p.Ala516Thr	missense_variant	4/4
KLHL33	XM_011536450.3	c.2338G>A	p.Ala780Thr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL33	ENST00000636854.3	c.2338G>A	p.Ala780Thr	missense_variant	5/5	5	NM_001365790.2	P1
KLHL33	ENST00000344581.4	c.1546G>A	p.Ala516Thr	missense_variant	4/4	5
KLHL33	ENST00000637228.1	c.*497G>A		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94485 AN: 152020 Hom.: 29715 Cov.: 34

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.644

GnomAD3 exomes AF: 0.591 AC: 92430 AN: 156406 Hom.: 27731 AF XY: 0.599 AC XY: 49661 AN XY: 82894

Gnomad AFR exome AF: 0.721

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.591

Gnomad EAS exome AF: 0.589

Gnomad SAS exome AF: 0.674

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.587 AC: 821111 AN: 1399298 Hom.: 242308 Cov.: 63 AF XY: 0.589 AC XY: 406780 AN XY: 690162

Gnomad4 AFR exome AF: 0.724

Gnomad4 AMR exome AF: 0.493

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.585

Gnomad4 SAS exome AF: 0.672

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.577

Gnomad4 OTH exome AF: 0.604

GnomAD4 genome AF: 0.622 AC: 94597 AN: 152138 Hom.: 29766 Cov.: 34 AF XY: 0.626 AC XY: 46523 AN XY: 74376

Gnomad4 AFR AF: 0.722

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.579

Gnomad4 EAS AF: 0.601

Gnomad4 SAS AF: 0.686

Gnomad4 FIN AF: 0.617

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.645

Alfa AF: 0.579 Hom.: 36213

Bravo AF: 0.619

TwinsUK AF: 0.593 AC: 2197

ALSPAC AF: 0.581 AC: 2241

ESP6500AA AF: 0.715 AC: 989

ESP6500EA AF: 0.577 AC: 1835

ExAC AF: 0.608 AC: 14960

Asia WGS AF: 0.624 AC: 2173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.55
Dann	Benign	0.29
DEOGEN2	Benign	0.0024	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.12	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
Polyphen		0.0010	.;B
Vest4		0.018
ClinPred		0.00059	T
GERP RS		-1.8
Varity_R		0.032
gMVP		0.27

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: rs7145318; hg19: chr14-20897064; COSMIC: COSV60726433;