13-33060846-C-T

Variant names:

• chr13-33060846-C-T
• rs564481
• NM_004795.4:c.1767C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004795.4(KL):​c.1767C>T​(p.His589His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,614,016 control chromosomes in the GnomAD database, including 122,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9096 hom., cov: 33)
  • Exomes 𝑓: 0.39 (113606 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.708
• Publications: 46 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-33060846-C-T is Benign according to our data. Variant chr13-33060846-C-T is described in ClinVar as Benign. ClinVar VariationId is 311698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.708 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

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.1767C>T	p.His589His	synonymous	Exon 4 of 5	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.1767C>T	p.His589His	synonymous	Exon 4 of 5	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.1825C>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47244 AN: 152056 Hom.: 9085 Cov.: 33

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.346

GnomAD2 exomes AF: 0.375 AC: 94398 AN: 251476 AF XY: 0.375

Gnomad AFR exome AF: 0.0792

Gnomad AMR exome AF: 0.542

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.155

Gnomad FIN exome AF: 0.377

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.388 AC: 566661 AN: 1461842 Hom.: 113606 Cov.: 58 AF XY: 0.387 AC XY: 281682 AN XY: 727222

African (AFR) AF: 0.0800 AC: 2677 AN: 33480

American (AMR) AF: 0.537 AC: 24023 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 11194 AN: 26136

East Asian (EAS) AF: 0.166 AC: 6604 AN: 39700

South Asian (SAS) AF: 0.344 AC: 29668 AN: 86258

European-Finnish (FIN) AF: 0.383 AC: 20470 AN: 53420

Middle Eastern (MID) AF: 0.400 AC: 2307 AN: 5768

European-Non Finnish (NFE) AF: 0.403 AC: 447579 AN: 1111962

Other (OTH) AF: 0.367 AC: 22139 AN: 60394

GnomAD4 genome AF: 0.311 AC: 47265 AN: 152174 Hom.: 9096 Cov.: 33 AF XY: 0.310 AC XY: 23066 AN XY: 74406

African (AFR) AF: 0.0897 AC: 3726 AN: 41546

American (AMR) AF: 0.460 AC: 7030 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1479 AN: 3472

East Asian (EAS) AF: 0.169 AC: 874 AN: 5162

South Asian (SAS) AF: 0.315 AC: 1519 AN: 4824

European-Finnish (FIN) AF: 0.380 AC: 4021 AN: 10578

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.403 AC: 27381 AN: 67982

Other (OTH) AF: 0.350 AC: 739 AN: 2110

Alfa AF: 0.343 Hom.: 4998

Bravo AF: 0.310

Asia WGS AF: 0.274 AC: 955 AN: 3478

EpiCase AF: 0.408

EpiControl AF: 0.404

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Tumoral calcinosis, hyperphosphatemic, familial, 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.63
DANN	Benign	0.31
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs564481; hg19: chr13-33634983; COSMIC: COSV66308637;