rs9527025

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004795.4(KL):c.1109G>C(p.Cys370Ser) variant causes a missense change. The variant allele was found at a frequency of 0.154 in 1,612,736 control chromosomes in the GnomAD database, including 20,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1945 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18467 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.06

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015380979).

BP6

Variant 13-33054056-G-C is Benign according to our data. Variant chr13-33054056-G-C is described in ClinVar as [Benign]. Clinvar id is 311691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KL	NM_004795.4 linkuse as main transcript	c.1109G>C	p.Cys370Ser	missense_variant	2/5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3 linkuse as main transcript	c.188G>C	p.Cys63Ser	missense_variant	2/5		XP_006719958.1
KL	XM_047430775.1 linkuse as main transcript	c.1109G>C	p.Cys370Ser	missense_variant	2/4		XP_047286731.1
KL	XM_047430776.1 linkuse as main transcript	c.1109G>C	p.Cys370Ser	missense_variant	2/4		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 linkuse as main transcript	c.1109G>C	p.Cys370Ser	missense_variant	2/5	1	NM_004795.4	ENSP00000369442	P1	Q9UEF7-1
KL	ENST00000487852.1 linkuse as main transcript	n.1117G>C		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23682

AN:

151786

Hom.:

1945

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.150

GnomAD3 exomes

AF:

0.141

AC:

35465

AN:

251066

Hom.:

2961

AF XY:

0.146

AC XY:

19862

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.0736

Gnomad ASJ exome

AF:

0.207

Gnomad EAS exome

AF:

0.00114

Gnomad SAS exome

AF:

0.176

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.152

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.154

AC:

225341

AN:

1460834

Hom.:

18467

Cov.:

AF XY:

0.155

AC XY:

112616

AN XY:

726730

show subpopulations

Gnomad4 AFR exome

AF:

0.178

Gnomad4 AMR exome

AF:

0.0771

Gnomad4 ASJ exome

AF:

0.208

Gnomad4 EAS exome

AF:

0.000856

Gnomad4 SAS exome

AF:

0.174

Gnomad4 FIN exome

AF:

0.198

Gnomad4 NFE exome

AF:

0.157

Gnomad4 OTH exome

AF:

0.165

GnomAD4 genome

AF:

0.156

AC:

23693

AN:

151902

Hom.:

1945

Cov.:

AF XY:

0.157

AC XY:

11660

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.183

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.216

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.193

Gnomad4 NFE

AF:

0.155

Gnomad4 OTH

AF:

0.149

Alfa

AF:

0.157

Hom.:

624

Bravo

AF:

0.148

TwinsUK

AF:

0.161

AC:

597

ALSPAC

AF:

0.168

AC:

649

ESP6500AA

AF:

0.185

AC:

816

ESP6500EA

AF:

0.164

AC:

1411

ExAC

AF:

0.143

AC:

17373

EpiCase

AF:

0.154

EpiControl

AF:

0.155

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 24217253, 11792841, 15677572, 29247834, 19421891) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.075

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-3.0

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.61

PROVEAN

Benign

4.0

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.083

MutPred

0.31

Gain of catalytic residue at C370 (P = 0);

MPC

0.15

ClinPred

0.0057

GERP RS

5.9

Varity_R

0.57

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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