Genetic Variant KLHL3:c.*3338dupT (chr5-137618759-C-CA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_017415.3(KLHL3):c.*3338dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 110,570 control chromosomes in the GnomAD database, including 58 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.030 ( 58 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0299 (3307/110570) while in subpopulation NFE AF = 0.0475 (2340/49222). AF 95% confidence interval is 0.0459. There are 58 homozygotes in GnomAd4. There are 1462 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 58 AD,AR gene

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.*3338dupT	3_prime_UTR	Exon 15 of 15	NP_059111.2	Q9UH77-1
KLHL3	NM_001257194.1		c.*3338dupT	3_prime_UTR	Exon 15 of 15	NP_001244123.1	Q9UH77-2
KLHL3	NM_001257195.2		c.*3338dupT	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.*3338dupT	3_prime_UTR	Exon 15 of 15	ENSP00000312397.4	Q9UH77-1
KLHL3	ENST00000508657.5	TSL:1	c.*3338dupT	3_prime_UTR	Exon 15 of 15	ENSP00000422099.1	Q9UH77-2
KLHL3	ENST00000506491.5	TSL:1	c.*3338dupT	3_prime_UTR	Exon 13 of 13	ENSP00000424828.1	Q9UH77-3

Frequencies

GnomAD3 genomes

AF:

0.0300

AC:

3313

AN:

110528

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.0137

Gnomad AMR

AF:

0.0197

Gnomad ASJ

AF:

0.00747

Gnomad EAS

AF:

0.0131

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0159

Gnomad MID

AF:

0.0365

Gnomad NFE

AF:

0.0476

Gnomad OTH

AF:

0.0195

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:

0.0299

AC:

3307

AN:

110570

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

1462

AN XY:

53026

show subpopulations

African (AFR)

AF:

0.0140

AC:

449

AN:

32122

American (AMR)

AF:

0.0197

AC:

211

AN:

10708

Ashkenazi Jewish (ASJ)

AF:

0.00747

AC:

AN:

2410

East Asian (EAS)

AF:

0.0129

AC:

AN:

4350

South Asian (SAS)

AF:

0.0264

AC:

AN:

3708

European-Finnish (FIN)

AF:

0.0159

AC:

AN:

5792

Middle Eastern (MID)

AF:

0.0333

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.0475

AC:

2340

AN:

49222

Other (OTH)

AF:

0.0194

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00489

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism

(source)

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

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5-137618759-CAAAA-CAAAAA

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