chr5-137617888-T-C

Variant names:

• chr5-137617888-T-C
• rs6863414
• NM_017415.3:c.*4210A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017415.3(KLHL3):​c.*4210A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 152,034 control chromosomes in the GnomAD database, including 32,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32801 hom., cov: 31)
  • Exomes 𝑓: 0.70 (32 hom.)
• Consequence: KLHL3 NM_017415.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.06
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-137617888-T-C is Benign according to our data. Variant chr5-137617888-T-C is described in ClinVar as Benign. ClinVar VariationId is 350923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.699 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.*4210A>G		3_prime_UTR	Exon 15 of 15	NP_059111.2	Q9UH77-1
	KLHL3	NM_001257194.1		c.*4210A>G		3_prime_UTR	Exon 15 of 15	NP_001244123.1	Q9UH77-2
	KLHL3	NM_001257195.2		c.*4210A>G		3_prime_UTR	Exon 13 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.*4210A>G		3_prime_UTR	Exon 15 of 15	ENSP00000312397.4	Q9UH77-1
	KLHL3	ENST00000508657.5	TSL:1	c.*4210A>G		3_prime_UTR	Exon 15 of 15	ENSP00000422099.1	Q9UH77-2
	KLHL3	ENST00000506491.5	TSL:1	c.*4210A>G		3_prime_UTR	Exon 13 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99336 AN: 151800 Hom.: 32789 Cov.: 31

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.674

GnomAD4 exome AF: 0.698 AC: 81 AN: 116 Hom.: 32 Cov.: 0 AF XY: 0.727 AC XY: 48 AN XY: 66

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.708 AC: 75 AN: 106

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.667 AC: 4 AN: 6

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.654 AC: 99392 AN: 151918 Hom.: 32801 Cov.: 31 AF XY: 0.659 AC XY: 48927 AN XY: 74270

African (AFR) AF: 0.597 AC: 24726 AN: 41392

American (AMR) AF: 0.665 AC: 10151 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2553 AN: 3468

East Asian (EAS) AF: 0.504 AC: 2599 AN: 5160

South Asian (SAS) AF: 0.719 AC: 3452 AN: 4804

European-Finnish (FIN) AF: 0.750 AC: 7920 AN: 10566

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.673 AC: 45706 AN: 67964

Other (OTH) AF: 0.669 AC: 1409 AN: 2106

Alfa AF: 0.552 Hom.: 1482

Bravo AF: 0.639

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.38
PhyloP100		-2.1
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: rs6863414; hg19: chr5-136953577; COSMIC: COSV59050712; COSMIC: COSV59050712;