Genetic Variant KL:p.Ala5Ala (chr13-33016455-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_004795.4(KL):c.15C>T(p.Ala5Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 964,242 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

KL
NM_004795.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.15

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:

LOC124903151 (HGNC:):

LOC124903151 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 13-33016455-C-T is Benign according to our data. Variant chr13-33016455-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 881364.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BP7

Synonymous conserved (PhyloP=-1.15 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4 link	c.15C>T	p.Ala5Ala	synonymous_variant	Exon 1 of 5	ENST00000380099.4	NP_004786.2	Q9UEF7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.15C>T	p.Ala5Ala	synonymous_variant	Exon 1 of 5	1	NM_004795.4	ENSP00000369442.3		Q9UEF7-1
KL	ENST00000487852.1 link	n.23C>T		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.000912

AC:

131

AN:

143650

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000297

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:

0.00181

Gnomad OTH

AF:

0.00100

GnomAD3 exomes

AF:

0.0156

AC:

AN:

Hom.:

AF XY:

0.0263

AC XY:

AN XY:

show subpopulations

Gnomad AMR exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00162

AC:

1328

AN:

820536

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

642

AN XY:

380462

show subpopulations

Gnomad4 AFR exome

AF:

0.000128

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00174

Gnomad4 OTH exome

AF:

0.000885

GnomAD4 genome

AF:

0.000912

AC:

131

AN:

143706

Hom.:

Cov.:

AF XY:

0.000616

AC XY:

AN XY:

69822

show subpopulations

Gnomad4 AFR

AF:

0.000296

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:

0.00181

Gnomad4 OTH

AF:

0.000996

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.000820

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tumoral calcinosis, hyperphosphatemic, familial, 3

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

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