13-33016580-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: KL NM_004795.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.403

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=0.0021276176).
• BP6: Variant 13-33016580-G-A is Benign according to our data. Variant chr13-33016580-G-A is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KL	NM_004795.4	c.140G>A	p.Arg47Gln	missense_variant	1/5	ENST00000380099.4
KL	XM_047430775.1	c.140G>A	p.Arg47Gln	missense_variant	1/4
KL	XM_047430776.1	c.140G>A	p.Arg47Gln	missense_variant	1/4
KL	XM_006719895.3	c.-103+267G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KL	ENST00000380099.4	c.140G>A	p.Arg47Gln	missense_variant	1/5	1	NM_004795.4	P1
KL	ENST00000487852.1	n.148G>A		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1648 AN: 151598 Hom.: 29 Cov.: 31

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

GnomAD3 exomes AF: 0.00252 AC: 216 AN: 85548 Hom.: 5 AF XY: 0.00205 AC XY: 95 AN XY: 46406

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 SAS 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.: 34 Cov.: 29 AF XY: 0.000991 AC XY: 646 AN XY: 651938

Gnomad4 AFR exome AF: 0.0391

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000289

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.0109 AC: 1649 AN: 151708 Hom.: 28 Cov.: 31 AF XY: 0.0107 AC XY: 794 AN XY: 74116

Gnomad4 AFR AF: 0.0359

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00579 Hom.: 3

Bravo AF: 0.0133

ESP6500AA AF: 0.0281 AC: 78

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 110

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.097
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	9.0
Dann	Benign	0.94
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.015
Sift	Benign	0.61	T
Sift4G	Benign	0.68	T
Polyphen		0.017	B
Vest4		0.075
MVP		0.37
MPC		1.1
ClinPred		0.0031	T
GERP RS		2.5
Varity_R		0.059
gMVP		0.28

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: rs201936594; hg19: chr13-33590718;