rs7145318

Variant names:

• chr14-20428905-C-T
• rs7145318
• NM_001365790.2:c.2338G>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.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. 16/21 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
• Publications: 27 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=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 rank	MANE	Protein	UniProt
KLHL33	NM_001365790.2	c.2338G>A	p.Ala780Thr	missense_variant	Exon 5 of 5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3	c.1546G>A	p.Ala516Thr	missense_variant	Exon 4 of 4		NP_001103467.2
KLHL33	XM_011536450.3	c.2338G>A	p.Ala780Thr	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.2338G>A	p.Ala780Thr	missense_variant	Exon 5 of 5	5	NM_001365790.2	ENSP00000490040.1

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

GnomAD2 exomes AF: 0.591 AC: 92430 AN: 156406 AF XY: 0.599

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 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

African (AFR) AF: 0.724 AC: 22885 AN: 31598

American (AMR) AF: 0.493 AC: 17585 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 15045 AN: 25180

East Asian (EAS) AF: 0.585 AC: 20898 AN: 35736

South Asian (SAS) AF: 0.672 AC: 53281 AN: 79232

European-Finnish (FIN) AF: 0.607 AC: 29902 AN: 49274

Middle Eastern (MID) AF: 0.663 AC: 3777 AN: 5698

European-Non Finnish (NFE) AF: 0.577 AC: 622724 AN: 1078878

Other (OTH) AF: 0.604 AC: 35014 AN: 58002

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

African (AFR) AF: 0.722 AC: 29963 AN: 41508

American (AMR) AF: 0.554 AC: 8462 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2009 AN: 3470

East Asian (EAS) AF: 0.601 AC: 3112 AN: 5174

South Asian (SAS) AF: 0.686 AC: 3314 AN: 4828

European-Finnish (FIN) AF: 0.617 AC: 6531 AN: 10592

Middle Eastern (MID) AF: 0.664 AC: 194 AN: 292

European-Non Finnish (NFE) AF: 0.575 AC: 39063 AN: 67962

Other (OTH) AF: 0.645 AC: 1362 AN: 2112

Alfa AF: 0.588 Hom.: 61000

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
MutationAssessor	Benign	1.1	.;L
PhyloP100		-0.88
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.22	.;N
REVEL	Benign	0.055
Sift	Benign	1.0	.;T
Sift4G	Benign	0.98	.;T
Polyphen		0.0010	.;B
Vest4		0.018
ClinPred		0.00059	T
GERP RS		-1.8
Varity_R		0.032
gMVP		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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