13-33016580-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004795.4(KL):c.140G>A(p.Arg47Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,483,644 control chromosomes in the GnomAD database, including 62 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 28 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 34 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.403

Publications

2 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

KL links:

LOC124903151 (HGNC:):

LOC124903151 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021276176).

BP6

Variant 13-33016580-G-A is Benign according to our data. Variant chr13-33016580-G-A is described in ClinVar as Benign. ClinVar VariationId is 311678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1649/151708) while in subpopulation AFR AF = 0.0359 (1487/41468). AF 95% confidence interval is 0.0343. There are 28 homozygotes in GnomAd4. There are 794 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004795.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	NM_004795.4	MANE Select	c.140G>A	p.Arg47Gln	missense	Exon 1 of 5	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.140G>A	p.Arg47Gln	missense	Exon 1 of 5	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.148G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1648

AN:

151598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000354

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00252

AC:

216

AN:

85548

AF XY:

0.00205

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.00316

GnomAD4 exome

AF:

0.00117

AC:

1556

AN:

1331936

Hom.:

Cov.:

AF XY:

0.000991

AC XY:

646

AN XY:

651938

show subpopulations

African (AFR)

AF:

0.0391

AC:

1087

AN:

27802

American (AMR)

AF:

0.00463

AC:

122

AN:

26334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21058

East Asian (EAS)

AF:

0.00

AC:

AN:

33352

South Asian (SAS)

AF:

0.0000289

AC:

AN:

69240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43174

Middle Eastern (MID)

AF:

0.00144

AC:

AN:

4852

European-Non Finnish (NFE)

AF:

0.000162

AC:

170

AN:

1051134

Other (OTH)

AF:

0.00306

AC:

168

AN:

54990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

165

247

330

412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0109

AC:

1649

AN:

151708

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

794

AN XY:

74116

show subpopulations

African (AFR)

AF:

0.0359

AC:

1487

AN:

41468

American (AMR)

AF:

0.00739

AC:

113

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5110

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10442

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000354

AC:

AN:

67808

Other (OTH)

AF:

0.0109

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00579

Hom.:

Bravo

AF:

0.0133

ESP6500AA

AF:

0.0281

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00118

AC:

110

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Tumoral calcinosis, hyperphosphatemic, familial, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.0

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

0.40

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

0.050

REVEL

Benign

0.015

Sift

Benign

0.61

Sift4G

Benign

0.68

Polyphen

0.017

Vest4

0.075

MVP

0.37

MPC

1.1

ClinPred

0.0031

GERP RS

2.5

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.059

gMVP

0.28

Mutation Taster

=97/3

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over