Genetic Variant KL:c.1599+603C>T (chr13-33055918-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004795.4(KL):c.1599+603C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 152,080 control chromosomes in the GnomAD database, including 23,056 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.54 ( 23056 hom., cov: 33)

Consequence

KL
NM_004795.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0130

Publications

9 publications found

Variant links:

Genes affected

KL (HGNC:6344): (klotho) This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]

KL Gene-Disease associations (from GenCC):

tumoral calcinosis, hyperphosphatemic, familial, 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tumoral calcinosis, hyperphosphatemic, familial, 3
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

KL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
KL	NM_004795.4 link	c.1599+603C>T	intron_variant	Intron 3 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3 link	c.678+603C>T	intron_variant	Intron 3 of 4		XP_006719958.1
KL	XM_047430775.1 link	c.1649+553C>T	intron_variant	Intron 3 of 3		XP_047286731.1
KL	XM_047430776.1 link	c.1649+553C>T	intron_variant	Intron 3 of 3		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.1599+603C>T		intron_variant	Intron 3 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1 link	n.1657+553C>T		intron_variant	Intron 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.543

AC:

82569

AN:

151962

Hom.:

23029

Cov.:

show subpopulations

Gnomad AFR

AF:

0.532

Gnomad AMI

AF:

0.516

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.649

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.473

Gnomad FIN

AF:

0.580

Gnomad MID

AF:

0.634

Gnomad NFE

AF:

0.563

Gnomad OTH

AF:

0.549

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

GnomAD4 genome

AF:

0.543

AC:

82648

AN:

152080

Hom.:

23056

Cov.:

AF XY:

0.541

AC XY:

40231

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.532

AC:

22055

AN:

41448

American (AMR)

AF:

0.586

AC:

8962

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.649

AC:

2253

AN:

3472

East Asian (EAS)

AF:

0.170

AC:

879

AN:

5178

South Asian (SAS)

AF:

0.474

AC:

2285

AN:

4824

European-Finnish (FIN)

AF:

0.580

AC:

6116

AN:

10550

Middle Eastern (MID)

AF:

0.634

AC:

185

AN:

292

European-Non Finnish (NFE)

AF:

0.563

AC:

38278

AN:

67994

Other (OTH)

AF:

0.552

AC:

1165

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1904

3808

5713

7617

9521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.560

Hom.:

12271

Bravo

AF:

0.544

Asia WGS

AF:

0.366

AC:

1279

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.91

(source)

DANN

Benign

0.39

PhyloP100

-0.013

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over