Genetic Variant NM_004795.4:c.15C>T (chr13-33016455-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 881364.

BP7

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

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

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.15C>T	p.Ala5Ala	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.15C>T	p.Ala5Ala	synonymous	Exon 1 of 5	ENSP00000369442.3	Q9UEF7-1
KL	ENST00000487852.1	TSL:5	n.23C>T		non_coding_transcript_exon	Exon 1 of 5
ENSG00000308044	ENST00000830674.1		n.-211G>A		upstream_gene	N/A

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

GnomAD2 exomes

AF:

0.0156

AC:

AN:

AF XY:

0.0263

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

African (AFR)

AF:

0.000128

AC:

AN:

15578

American (AMR)

AF:

0.00

AC:

AN:

1286

Ashkenazi Jewish (ASJ)

AF:

0.000192

AC:

AN:

5212

East Asian (EAS)

AF:

0.00

AC:

AN:

3894

South Asian (SAS)

AF:

0.00

AC:

AN:

16916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1594

European-Non Finnish (NFE)

AF:

0.00174

AC:

1301

AN:

747762

Other (OTH)

AF:

0.000885

AC:

AN:

27126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

131

197

262

328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000912

AC:

131

AN:

143706

Hom.:

Cov.:

AF XY:

0.000616

AC XY:

AN XY:

69822

show subpopulations

African (AFR)

AF:

0.000296

AC:

AN:

40502

American (AMR)

AF:

0.00

AC:

AN:

14582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3338

East Asian (EAS)

AF:

0.00

AC:

AN:

4854

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00181

AC:

117

AN:

64738

Other (OTH)

AF:

0.000996

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.000820

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Tumoral calcinosis, hyperphosphatemic, familial, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

-1.1

PromoterAI

0.024

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over