rs757157

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

KLHL3 Gene-Disease associations (from GenCC):

• pseudohypoaldosteronism type 2D

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017415.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	NM_017415.3	MANE Select	c.*4780A>G		downstream_gene	N/A	NP_059111.2
	KLHL3	NM_001257194.1		c.*4780A>G		downstream_gene	N/A	NP_001244123.1
	KLHL3	NM_001257195.2		c.*4780A>G		downstream_gene	N/A	NP_001244124.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	ENST00000309755.9	TSL:1 MANE Select	c.*4780A>G		downstream_gene	N/A	ENSP00000312397.4
	KLHL3	ENST00000508657.5	TSL:1	c.*4780A>G		downstream_gene	N/A	ENSP00000422099.1
	KLHL3	ENST00000506491.5	TSL:1	c.*4780A>G		downstream_gene	N/A	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

African (AFR) AF: 0.213 AC: 8789 AN: 41342

American (AMR) AF: 0.439 AC: 6707 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2230 AN: 3462

East Asian (EAS) AF: 0.0578 AC: 299 AN: 5176

South Asian (SAS) AF: 0.393 AC: 1897 AN: 4826

European-Finnish (FIN) AF: 0.642 AC: 6790 AN: 10578

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37850 AN: 67970

Other (OTH) AF: 0.459 AC: 970 AN: 2112

Alfa AF: 0.503 Hom.: 54957

Bravo AF: 0.407

Asia WGS AF: 0.255 AC: 891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.61
PhyloP100		-0.84

Splicing

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

Other links and lift over

dbSNP: rs757157; hg19: chr5-136953007;