rs757157

Variant names:

• chr5-137617318-T-C
• rs757157
• NM_017415.3:c.*4780A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017415.3(KLHL3):​c.*4780A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 151,946 control chromosomes in the GnomAD database, including 16,751 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (16751 hom., cov: 32)
• Consequence: KLHL3 NM_017415.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.845

Genes affected

KLHL3 (HGNC:6354): (kelch like family member 3) This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex. Muatations in this gene cause pseudohypoaldosteronism type IID (PHA2D); a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL3	NM_017415.3	c.*4780A>G		downstream_gene_variant		ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1	c.*4780A>G		downstream_gene_variant			NP_001244123.1
KLHL3	NM_001257195.2	c.*4780A>G		downstream_gene_variant			NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755.9	c.*4780A>G		downstream_gene_variant		1	NM_017415.3	ENSP00000312397.4
KLHL3	ENST00000508657.5	c.*4780A>G		downstream_gene_variant		1		ENSP00000422099.1
KLHL3	ENST00000506491.5	c.*4780A>G		downstream_gene_variant		1		ENSP00000424828.1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66237 AN: 151828 Hom.: 16756 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.0572

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.464

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.436 AC: 66246 AN: 151946 Hom.: 16751 Cov.: 32 AF XY: 0.436 AC XY: 32406 AN XY: 74280

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.644

Gnomad4 EAS AF: 0.0578

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.642

Gnomad4 NFE AF: 0.557

Gnomad4 OTH AF: 0.459

Alfa AF: 0.527 Hom.: 36310

Bravo AF: 0.407

Asia WGS AF: 0.255 AC: 891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs757157; hg19: chr5-136953007;