Genetic Variant KL:p.Ser4Ser (chr13-33016452-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_004795.4(KL):c.12C>T(p.Ser4Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000709 in 141,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KL
NM_004795.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.308

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

tumoral calcinosis, hyperphosphatemic, familial, 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tumoral calcinosis, hyperphosphatemic, familial, 3
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

KL links:

LOC124903151 (HGNC:):

LOC124903151 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 13-33016452-C-T is Benign according to our data. Variant chr13-33016452-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1982811.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.308 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	NM_004795.4	MANE Select	c.12C>T	p.Ser4Ser	synonymous	Exon 1 of 5	NP_004786.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KL	ENST00000380099.4	TSL:1 MANE Select	c.12C>T	p.Ser4Ser	synonymous	Exon 1 of 5	ENSP00000369442.3	Q9UEF7-1
KL	ENST00000487852.1	TSL:5	n.20C>T		non_coding_transcript_exon	Exon 1 of 5
ENSG00000308044	ENST00000830674.1		n.-208G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000709

AC:

AN:

141080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000690

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

814262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

377444

African (AFR)

AF:

0.00

AC:

AN:

15466

American (AMR)

AF:

0.00

AC:

AN:

1214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5130

East Asian (EAS)

AF:

0.00

AC:

AN:

3746

South Asian (SAS)

AF:

0.00

AC:

AN:

16808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

742462

Other (OTH)

AF:

0.00

AC:

AN:

26888

GnomAD4 genome

AF:

0.00000709

AC:

AN:

141080

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40208

American (AMR)

AF:

0.0000690

AC:

AN:

14488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3270

East Asian (EAS)

AF:

0.00

AC:

AN:

4640

South Asian (SAS)

AF:

0.00

AC:

AN:

4580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63520

Other (OTH)

AF:

0.00

AC:

AN:

1962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

-0.31

PromoterAI

-0.047

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over