chr5-137625877-C-A

Variant names:

• chr5-137625877-C-A
• rs17171525
• NM_017415.3:c.1611G>T

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.1611G>T​(p.Gly537Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,614,148 control chromosomes in the GnomAD database, including 2,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (221 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1850 hom.)
• Consequence: KLHL3 NM_017415.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.184
• Publications: 6 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 5-137625877-C-A is Benign according to our data. Variant chr5-137625877-C-A is described in ClinVar as Benign. ClinVar VariationId is 260808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.184 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 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.1611G>T	p.Gly537Gly	synonymous	Exon 14 of 15	NP_059111.2	Q9UH77-1
	KLHL3	NM_001257194.1		c.1515G>T	p.Gly505Gly	synonymous	Exon 14 of 15	NP_001244123.1	Q9UH77-2
	KLHL3	NM_001257195.2		c.1365G>T	p.Gly455Gly	synonymous	Exon 12 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.1611G>T	p.Gly537Gly	synonymous	Exon 14 of 15	ENSP00000312397.4	Q9UH77-1
	KLHL3	ENST00000508657.5	TSL:1	c.1515G>T	p.Gly505Gly	synonymous	Exon 14 of 15	ENSP00000422099.1	Q9UH77-2
	KLHL3	ENST00000506491.5	TSL:1	c.1365G>T	p.Gly455Gly	synonymous	Exon 12 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5524 AN: 152186 Hom.: 218 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0422

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0484 AC: 12160 AN: 251402 AF XY: 0.0429

Gnomad AFR exome AF: 0.00966

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0386

GnomAD4 exome AF: 0.0420 AC: 61351 AN: 1461844 Hom.: 1850 Cov.: 32 AF XY: 0.0403 AC XY: 29328 AN XY: 727222

African (AFR) AF: 0.00789 AC: 264 AN: 33480

American (AMR) AF: 0.171 AC: 7629 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0223 AC: 583 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.0184 AC: 1587 AN: 86258

European-Finnish (FIN) AF: 0.0233 AC: 1246 AN: 53416

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.0430 AC: 47859 AN: 1111966

Other (OTH) AF: 0.0353 AC: 2130 AN: 60396

GnomAD4 genome AF: 0.0363 AC: 5533 AN: 152304 Hom.: 221 Cov.: 32 AF XY: 0.0364 AC XY: 2712 AN XY: 74488

African (AFR) AF: 0.0113 AC: 470 AN: 41554

American (AMR) AF: 0.114 AC: 1739 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4828

European-Finnish (FIN) AF: 0.0198 AC: 210 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0422 AC: 2869 AN: 68026

Other (OTH) AF: 0.0425 AC: 90 AN: 2116

Alfa AF: 0.0389 Hom.: 500

Bravo AF: 0.0430

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.0360

EpiControl AF: 0.0332

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	7.5
DANN	Benign	0.67
PhyloP100		0.18
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17171525; hg19: chr5-136961566; COSMIC: COSV59059161;