chr5-137618889-ATT-A

Variant names:

• chr5-137618889-ATT-A
• rs369833337
• NM_017415.3:c.*3207_*3208delAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_017415.3(KLHL3):​c.*3207_*3208delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (29463 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: KLHL3 NM_017415.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.308

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL3	NM_017415.3	c.*3207_*3208delAA		3_prime_UTR_variant	Exon 15 of 15	ENST00000309755.9	NP_059111.2
KLHL3	NM_001257194.1	c.*3207_*3208delAA		3_prime_UTR_variant	Exon 15 of 15		NP_001244123.1
KLHL3	NM_001257195.2	c.*3207_*3208delAA		3_prime_UTR_variant	Exon 13 of 13		NP_001244124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL3	ENST00000309755	c.*3207_*3208delAA		3_prime_UTR_variant	Exon 15 of 15	1	NM_017415.3	ENSP00000312397.4
KLHL3	ENST00000508657	c.*3207_*3208delAA		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000422099.1
KLHL3	ENST00000506491	c.*3207_*3208delAA		3_prime_UTR_variant	Exon 13 of 13	1		ENSP00000424828.1
KLHL3	ENST00000509694.1	n.623-1027_623-1026delAA		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.635 AC: 91697 AN: 144368 Hom.: 29478 Cov.: 0

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.664

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.653

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

GnomAD4 genome AF: 0.635 AC: 91676 AN: 144392 Hom.: 29463 Cov.: 0 AF XY: 0.637 AC XY: 44497 AN XY: 69822

Gnomad4 AFR AF: 0.554

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.726

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.708

Gnomad4 FIN AF: 0.710

Gnomad4 NFE AF: 0.671

Gnomad4 OTH AF: 0.649

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs369833337; hg19: chr5-136954578;