NM_017415.3:c.471A>G

Variant names:

• chr5-137692340-T-C
• rs2905608
• NM_017415.3:c.471A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017415.3(KLHL3):​c.471A>G​(p.Ala157Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 1,613,152 control chromosomes in the GnomAD database, including 486,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A157A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.78 (46674 hom., cov: 33)
  • Exomes 𝑓: 0.77 (439693 hom.)
• Consequence: KLHL3 NM_017415.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.98
• Publications: 21 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000295218 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.145).
• BP6: Variant 5-137692340-T-C is Benign according to our data. Variant chr5-137692340-T-C is described in ClinVar as Benign. ClinVar VariationId is 260809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	NM_017415.3	MANE Select	c.471A>G	p.Ala157Ala	synonymous	Exon 5 of 15	NP_059111.2	Q9UH77-1
	KLHL3	NM_001257194.1		c.375A>G	p.Ala125Ala	synonymous	Exon 5 of 15	NP_001244123.1	Q9UH77-2
	KLHL3	NM_001257195.2		c.225A>G	p.Ala75Ala	synonymous	Exon 3 of 13	NP_001244124.1	Q9UH77-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL3	ENST00000309755.9	TSL:1 MANE Select	c.471A>G	p.Ala157Ala	synonymous	Exon 5 of 15	ENSP00000312397.4	Q9UH77-1
	KLHL3	ENST00000508657.5	TSL:1	c.375A>G	p.Ala125Ala	synonymous	Exon 5 of 15	ENSP00000422099.1	Q9UH77-2
	KLHL3	ENST00000506491.5	TSL:1	c.225A>G	p.Ala75Ala	synonymous	Exon 3 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118770 AN: 152082 Hom.: 46621 Cov.: 33

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.815

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.763

GnomAD2 exomes AF: 0.793 AC: 198470 AN: 250382 AF XY: 0.791

Gnomad AFR exome AF: 0.803

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.991

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.775 AC: 1131763 AN: 1460952 Hom.: 439693 Cov.: 50 AF XY: 0.775 AC XY: 563216 AN XY: 726750

African (AFR) AF: 0.801 AC: 26807 AN: 33462

American (AMR) AF: 0.808 AC: 36066 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 18931 AN: 26128

East Asian (EAS) AF: 0.973 AC: 38642 AN: 39696

South Asian (SAS) AF: 0.811 AC: 69874 AN: 86202

European-Finnish (FIN) AF: 0.760 AC: 40603 AN: 53398

Middle Eastern (MID) AF: 0.748 AC: 4060 AN: 5430

European-Non Finnish (NFE) AF: 0.765 AC: 849943 AN: 1111642

Other (OTH) AF: 0.776 AC: 46837 AN: 60334

GnomAD4 genome AF: 0.781 AC: 118885 AN: 152200 Hom.: 46674 Cov.: 33 AF XY: 0.782 AC XY: 58211 AN XY: 74426

African (AFR) AF: 0.799 AC: 33203 AN: 41532

American (AMR) AF: 0.781 AC: 11951 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2523 AN: 3472

East Asian (EAS) AF: 0.984 AC: 5091 AN: 5176

South Asian (SAS) AF: 0.815 AC: 3933 AN: 4828

European-Finnish (FIN) AF: 0.759 AC: 8040 AN: 10592

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51747 AN: 67992

Other (OTH) AF: 0.766 AC: 1615 AN: 2108

Alfa AF: 0.749 Hom.: 14982

Bravo AF: 0.784

Asia WGS AF: 0.866 AC: 3012 AN: 3478

EpiCase AF: 0.766

EpiControl AF: 0.758

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Pseudohypoaldosteronism type 2D (2)
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0070
DANN	Benign	0.74
PhyloP100		-4.0
Mutation Taster		=69/31	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: rs2905608; hg19: chr5-137028029; COSMIC: COSV59052799;