Variant 13-33016520-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004795.4(KL):c.80G>A(p.Gly27Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 1,331,618 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

KL
NM_004795.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.608

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09790105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KL	NM_004795.4 linkuse as main transcript	c.80G>A	p.Gly27Asp	missense_variant	1/5	ENST00000380099.4	NP_004786.2
KL	XM_047430775.1 linkuse as main transcript	c.80G>A	p.Gly27Asp	missense_variant	1/4		XP_047286731.1
KL	XM_047430776.1 linkuse as main transcript	c.80G>A	p.Gly27Asp	missense_variant	1/4		XP_047286732.1
KL	XM_006719895.3 linkuse as main transcript	c.-103+207G>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.80G>A	p.Gly27Asp	missense_variant	1/5	1	NM_004795.4	ENSP00000369442	P1	Q9UEF7-1
KL	ENST00000487852.1 linkuse as main transcript	n.88G>A		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

149832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000254

AC:

AN:

1181786

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

568922

show subpopulations

Gnomad4 AFR exome

AF:

0.0000431

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000204

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000667

AC:

AN:

149832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73118

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.80G>A (p.G27D) alteration is located in exon 1 (coding exon 1) of the KL gene. This alteration results from a G to A substitution at nucleotide position 80, causing the glycine (G) at amino acid position 27 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.25

M_CAP

Benign

0.046

MetaRNN

Benign

0.098

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.18

REVEL

Benign

0.059

Sift

Benign

0.14

Sift4G

Benign

0.25

Polyphen

0.089

Vest4

0.31

MutPred

0.33

Gain of loop (P = 0.0166);

MVP

0.19

MPC

1.2

ClinPred

0.047

GERP RS

0.15

Varity_R

0.089

gMVP

0.41

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