Genetic Variant KLHL3:c.*3337_*3338dupTT (chr5-137618759-C-CAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017415.3(KLHL3):c.*3337_*3338dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 110,640 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KLHL3
NM_017415.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.572

Publications

1 publications found

Variant links:

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

KLHL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KLHL3	NM_017415.3	MANE Select	c.3337_3338dupTT	3_prime_UTR	Exon 15 of 15	NP_059111.2	Q9UH77-1
KLHL3	NM_001257194.1		c.3337_3338dupTT	3_prime_UTR	Exon 15 of 15	NP_001244123.1	Q9UH77-2
KLHL3	NM_001257195.2		c.3337_3338dupTT	3_prime_UTR	Exon 13 of 13	NP_001244124.1	Q9UH77-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KLHL3	ENST00000309755.9	TSL:1 MANE Select	c.3337_3338dupTT	3_prime_UTR	Exon 15 of 15	ENSP00000312397.4	Q9UH77-1
KLHL3	ENST00000508657.5	TSL:1	c.3337_3338dupTT	3_prime_UTR	Exon 15 of 15	ENSP00000422099.1	Q9UH77-2
KLHL3	ENST00000506491.5	TSL:1	c.3337_3338dupTT	3_prime_UTR	Exon 13 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000406

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110640

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

53060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32128

American (AMR)

AF:

0.00

AC:

AN:

10712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2410

East Asian (EAS)

AF:

0.00

AC:

AN:

4350

South Asian (SAS)

AF:

0.00

AC:

AN:

3708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.0000406

AC:

AN:

49278

Other (OTH)

AF:

0.00

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.57

Splicing

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

Publications

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5-137618759-CAAAA-CAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over