rs121908423

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_004795.4(KL):c.578A>G(p.His193Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000313 in 1,596,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 5.12

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 13-33017018-A-G is Pathogenic according to our data. Variant chr13-33017018-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5346.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4 link	c.578A>G	p.His193Arg	missense_variant	Exon 1 of 5	ENST00000380099.4	NP_004786.2	Q9UEF7-1
KL	XM_047430775.1 link	c.578A>G	p.His193Arg	missense_variant	Exon 1 of 4		XP_047286731.1
KL	XM_047430776.1 link	c.578A>G	p.His193Arg	missense_variant	Exon 1 of 4		XP_047286732.1
KL	XM_006719895.3 link	c.-103+705A>G		intron_variant	Intron 1 of 4		XP_006719958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.578A>G	p.His193Arg	missense_variant	Exon 1 of 5	1	NM_004795.4	ENSP00000369442.3		Q9UEF7-1
KL	ENST00000487852.1 link	n.586A>G		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000477

AC:

AN:

209530

Hom.:

AF XY:

0.00000858

AC XY:

AN XY:

116508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1444222

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000314

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tumoral calcinosis, hyperphosphatemic, familial, 3

Pathogenic:2

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Tumoral calcinosis, hyperphosphatemic, familial, 3, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/17710231). -

Sep 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Uncertain:1

Jul 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 5346). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 193 of the KL protein (p.His193Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with tumoral calcinosis (PMID: 17710231). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KL protein function. Experimental studies have shown that this missense change affects KL function (PMID: 17710231). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Tumoral calcinosis, hyperphosphatemic, familial, 1

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

4.2

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MutPred

0.85

Gain of catalytic residue at P197 (P = 0.0048);

MVP

0.95

MPC

2.3

ClinPred

1.0

GERP RS

4.0

Varity_R

0.99

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over