13-33016580-G-A

Position:

chr13-33016580-G-A

Variant summary

Our verdict is Benign. Variant got -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. 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.403

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=0.0021276176).

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 GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KL	NM_004795.4 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	1/5	ENST00000380099.4	NP_004786.2
KL	XM_047430775.1 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	1/4		XP_047286731.1
KL	XM_047430776.1 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	1/4		XP_047286732.1
KL	XM_006719895.3 linkuse as main transcript	c.-103+267G>A		intron_variant			XP_006719958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	1/5	1	NM_004795.4	ENSP00000369442	P1	Q9UEF7-1
KL	ENST00000487852.1 linkuse as main transcript	n.148G>A		non_coding_transcript_exon_variant	1/5	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

GnomAD3 exomes

AF:

0.00252

AC:

216

AN:

85548

Hom.:

AF XY:

0.00205

AC XY:

AN XY:

46406

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 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.:

Cov.:

AF XY:

0.000991

AC XY:

646

AN XY:

651938

show subpopulations

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.:

Cov.:

AF XY:

0.0107

AC XY:

794

AN XY:

74116

show subpopulations

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.:

Bravo

AF:

0.0133

ESP6500AA

AF:

0.0281

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00118

AC:

110

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.0

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

MutationTaster

Benign

1.0

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

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

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