13-33016589-C-T

Position:

chr13-33016589-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004795.4(KL):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,496,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0420

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_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026478797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KL	NM_004795.4 linkuse as main transcript	c.149C>T	p.Ala50Val	missense_variant	1/5	ENST00000380099.4	NP_004786.2
KL	XM_047430775.1 linkuse as main transcript	c.149C>T	p.Ala50Val	missense_variant	1/4		XP_047286731.1
KL	XM_047430776.1 linkuse as main transcript	c.149C>T	p.Ala50Val	missense_variant	1/4		XP_047286732.1
KL	XM_006719895.3 linkuse as main transcript	c.-103+276C>T		intron_variant			XP_006719958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 linkuse as main transcript	c.149C>T	p.Ala50Val	missense_variant	1/5	1	NM_004795.4	ENSP00000369442	P1	Q9UEF7-1
KL	ENST00000487852.1 linkuse as main transcript	n.157C>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151730

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:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000305

AC:

AN:

98234

Hom.:

AF XY:

0.0000376

AC XY:

AN XY:

53128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000372

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1344958

Hom.:

Cov.:

AF XY:

0.0000212

AC XY:

AN XY:

658938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000117

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000225

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151730

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74060

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with KL-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.04%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 50 of the KL protein (p.Ala50Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.0

DANN

Benign

0.83

DEOGEN2

Benign

0.087

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.36

M_CAP

Benign

0.036

MetaRNN

Benign

0.026

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

0.26

REVEL

Benign

0.016

Sift

Benign

0.67

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.051

MutPred

0.36

Gain of catalytic residue at P48 (P = 0.001);

MVP

0.26

MPC

0.94

ClinPred

0.013

GERP RS

0.38

Varity_R

0.075

gMVP

0.36

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