13-33054056-G-C

Variant names:

• chr13-33054056-G-C
• rs9527025
• NM_004795.4:c.1109G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.06
• Publications: 85 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	NM_004795.4	MANE Select	c.1109G>C	p.Cys370Ser	missense	Exon 2 of 5	NP_004786.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.1109G>C	p.Cys370Ser	missense	Exon 2 of 5	ENSP00000369442.3
	KL	ENST00000487852.1	TSL:5	n.1117G>C		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23682 AN: 151786 Hom.: 1945 Cov.: 32

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

GnomAD2 exomes AF: 0.141 AC: 35465 AN: 251066 AF XY: 0.146

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 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.: 34 AF XY: 0.155 AC XY: 112616 AN XY: 726730

African (AFR) AF: 0.178 AC: 5950 AN: 33398

American (AMR) AF: 0.0771 AC: 3439 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5438 AN: 26116

East Asian (EAS) AF: 0.000856 AC: 34 AN: 39698

South Asian (SAS) AF: 0.174 AC: 14997 AN: 86196

European-Finnish (FIN) AF: 0.198 AC: 10552 AN: 53358

Middle Eastern (MID) AF: 0.163 AC: 937 AN: 5762

European-Non Finnish (NFE) AF: 0.157 AC: 174045 AN: 1111338

Other (OTH) AF: 0.165 AC: 9949 AN: 60340

GnomAD4 genome AF: 0.156 AC: 23693 AN: 151902 Hom.: 1945 Cov.: 32 AF XY: 0.157 AC XY: 11660 AN XY: 74228

African (AFR) AF: 0.183 AC: 7589 AN: 41428

American (AMR) AF: 0.103 AC: 1566 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3468

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5168

South Asian (SAS) AF: 0.162 AC: 775 AN: 4794

European-Finnish (FIN) AF: 0.193 AC: 2034 AN: 10526

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.155 AC: 10525 AN: 67956

Other (OTH) AF: 0.149 AC: 311 AN: 2094

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

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24217253, 11792841, 15677572, 29247834, 19421891)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.52
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-3.0	N
PhyloP100		6.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	4.0	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.31		Gain of catalytic residue at C370 (P = 0)
MPC		0.15
ClinPred		0.0057	T
GERP RS		5.9
Varity_R		0.57
gMVP		0.71
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9527025; hg19: chr13-33628193; COSMIC: COSV66309390;