13-33016531-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004795.4(KL):c.91C>T(p.Leu31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,351,012 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (5 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.222

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 13-33016531-C-T is Benign according to our data. Variant chr13-33016531-C-T is described in ClinVar as [Benign]. Clinvar id is 881809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.222 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KL	NM_004795.4	c.91C>T	p.Leu31=	synonymous_variant	1/5	ENST00000380099.4
KL	XM_047430775.1	c.91C>T	p.Leu31=	synonymous_variant	1/4
KL	XM_047430776.1	c.91C>T	p.Leu31=	synonymous_variant	1/4
KL	XM_006719895.3	c.-103+218C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KL	ENST00000380099.4	c.91C>T	p.Leu31=	synonymous_variant	1/5	1	NM_004795.4	P1
KL	ENST00000487852.1	n.99C>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 582 AN: 150538 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000727

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: 0.0000148

Gnomad OTH AF: 0.00434

GnomAD3 exomes AF: 0.000372 AC: 5 AN: 13458 Hom.: 0 AF XY: 0.000241 AC XY: 2 AN XY: 8296

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.00134

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: 0.00

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.000337 AC: 404 AN: 1200368 Hom.: 5 Cov.: 28 AF XY: 0.000314 AC XY: 182 AN XY: 579480

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.000376

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: 0.00000101

Gnomad4 OTH exome AF: 0.000830

GnomAD4 genome AF: 0.00386 AC: 581 AN: 150644 Hom.: 7 Cov.: 31 AF XY: 0.00370 AC XY: 272 AN XY: 73584

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.000726

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00429

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00417

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 16, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	9.4
Dann	Benign	0.95

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

Other links and lift over

dbSNP: rs540806300; hg19: chr13-33590669;