rs3752472

chr13-33055256-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004795.4(KL):c.1540C>T(p.Pro514Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0093 in 1,614,160 control chromosomes in the GnomAD database, including 692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (92 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (600 hom.)
• Consequence: KL NM_004795.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.73

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018047988).
• BP6: Variant 13-33055256-C-T is Benign according to our data. Variant chr13-33055256-C-T is described in ClinVar as [Benign]. Clinvar id is 311695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-33055256-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KL	NM_004795.4	c.1540C>T	p.Pro514Ser	missense_variant	3/5	ENST00000380099.4
KL	XM_006719895.3	c.619C>T	p.Pro207Ser	missense_variant	3/5
KL	XM_047430775.1	c.1540C>T	p.Pro514Ser	missense_variant	3/4
KL	XM_047430776.1	c.1540C>T	p.Pro514Ser	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KL	ENST00000380099.4	c.1540C>T	p.Pro514Ser	missense_variant	3/5	1	NM_004795.4	P1
KL	ENST00000487852.1	n.1548C>T		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2416 AN: 152176 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0670

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.0823

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0293 AC: 7356 AN: 251440 Hom.: 432 AF XY: 0.0243 AC XY: 3298 AN XY: 135894

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0851

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.00861 AC: 12584 AN: 1461866 Hom.: 600 Cov.: 32 AF XY: 0.00826 AC XY: 6010 AN XY: 727238

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.00979

Gnomad4 EAS exome AF: 0.0847

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.000606

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0159 AC: 2426 AN: 152294 Hom.: 92 Cov.: 32 AF XY: 0.0183 AC XY: 1364 AN XY: 74466

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.0674

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.0827

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00544 Hom.: 48

Bravo AF: 0.0212

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.0259 AC: 3140

Asia WGS AF: 0.0530 AC: 185 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.19
Sift	Benign	0.21	T
Sift4G	Uncertain	0.051	T
Polyphen		0.40	B
Vest4		0.22
MPC		0.14
ClinPred		0.017	T
GERP RS		6.0
Varity_R		0.30
gMVP		0.81

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

Other links and lift over

dbSNP: rs3752472; hg19: chr13-33629393; COSMIC: COSV66308190;