chr13-33054001-T-G

Position:

chr13-33054001-T-G

Variant summary

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

The NM_004795.4(KL):c.1054T>G(p.Phe352Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,612,748 control chromosomes in the GnomAD database, including 20,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1938 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18471 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.89

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=0.0017518401).

BP6

Variant 13-33054001-T-G is Benign according to our data. Variant chr13-33054001-T-G is described in ClinVar as [Benign]. Clinvar id is 311690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 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.1054T>G	p.Phe352Val	missense_variant	2/5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3 linkuse as main transcript	c.133T>G	p.Phe45Val	missense_variant	2/5		XP_006719958.1
KL	XM_047430775.1 linkuse as main transcript	c.1054T>G	p.Phe352Val	missense_variant	2/4		XP_047286731.1
KL	XM_047430776.1 linkuse as main transcript	c.1054T>G	p.Phe352Val	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.1054T>G	p.Phe352Val	missense_variant	2/5	1	NM_004795.4	ENSP00000369442	P1	Q9UEF7-1
KL	ENST00000487852.1 linkuse as main transcript	n.1062T>G		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23680

AN:

151982

Hom.:

1937

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:

0.000770

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.149

GnomAD3 exomes

AF:

0.141

AC:

35479

AN:

251294

Hom.:

2957

AF XY:

0.146

AC XY:

19876

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.0735

Gnomad ASJ exome

AF:

0.206

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:

225219

AN:

1460648

Hom.:

18471

Cov.:

AF XY:

0.155

AC XY:

112556

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.178

Gnomad4 AMR exome

AF:

0.0769

Gnomad4 ASJ exome

AF:

0.208

Gnomad4 EAS exome

AF:

0.000857

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:

152100

Hom.:

1938

Cov.:

AF XY:

0.157

AC XY:

11658

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.183

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.216

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.192

Gnomad4 NFE

AF:

0.155

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.147

Hom.:

4015

Bravo

AF:

0.148

TwinsUK

AF:

0.161

AC:

597

ALSPAC

AF:

0.169

AC:

650

ESP6500AA

AF:

0.185

AC:

816

ESP6500EA

AF:

0.164

AC:

1411

ExAC

AF:

0.143

AC:

17372

Asia WGS

AF:

0.0750

AC:

264

AN:

3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 19421891, 29247834, 15677572, 11792841, 19802015, 24217253, 21376714, 21093413) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

MutationTaster

Benign

2.7e-11

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.33

MPC

0.66

ClinPred

0.022

GERP RS

5.9

Varity_R

0.96

gMVP

0.95

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