rs650439

Variant names:

• chr13-33061802-T-A
• rs650439
• NM_004795.4:c.2701+22T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004795.4(KL):​c.2701+22T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 1,609,134 control chromosomes in the GnomAD database, including 570,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50275 hom., cov: 31)
  • Exomes 𝑓: 0.84 (520598 hom.)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.97
• Publications: 27 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: AR, Unknown Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 13-33061802-T-A is Benign according to our data. Variant chr13-33061802-T-A is described in ClinVar as Benign. ClinVar VariationId is 1222763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.2701+22T>A		intron_variant	Intron 4 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.1780+22T>A		intron_variant	Intron 4 of 4		XP_006719958.1
KL	XM_047430776.1	c.*1123T>A		downstream_gene_variant			XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.2701+22T>A		intron_variant	Intron 4 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.2759+22T>A		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes AF: 0.809 AC: 123066 AN: 152040 Hom.: 50237 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.856

Gnomad OTH AF: 0.838

GnomAD2 exomes AF: 0.819 AC: 200289 AN: 244550 AF XY: 0.823

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.796

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.602

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.857

Gnomad OTH exome AF: 0.842

GnomAD4 exome AF: 0.844 AC: 1229547 AN: 1456976 Hom.: 520598 Cov.: 38 AF XY: 0.844 AC XY: 611919 AN XY: 724878

African (AFR) AF: 0.725 AC: 24237 AN: 33444

American (AMR) AF: 0.803 AC: 35910 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 23781 AN: 26126

East Asian (EAS) AF: 0.627 AC: 24875 AN: 39684

South Asian (SAS) AF: 0.815 AC: 70251 AN: 86190

European-Finnish (FIN) AF: 0.882 AC: 43654 AN: 49472

Middle Eastern (MID) AF: 0.854 AC: 4924 AN: 5768

European-Non Finnish (NFE) AF: 0.856 AC: 951603 AN: 1111238

Other (OTH) AF: 0.834 AC: 50312 AN: 60336

GnomAD4 genome AF: 0.809 AC: 123154 AN: 152158 Hom.: 50275 Cov.: 31 AF XY: 0.809 AC XY: 60155 AN XY: 74380

African (AFR) AF: 0.726 AC: 30116 AN: 41492

American (AMR) AF: 0.812 AC: 12411 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3169 AN: 3472

East Asian (EAS) AF: 0.615 AC: 3176 AN: 5162

South Asian (SAS) AF: 0.803 AC: 3867 AN: 4814

European-Finnish (FIN) AF: 0.885 AC: 9383 AN: 10604

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.856 AC: 58200 AN: 68002

Other (OTH) AF: 0.837 AC: 1770 AN: 2114

Alfa AF: 0.840 Hom.: 9922

Bravo AF: 0.803

Asia WGS AF: 0.712 AC: 2479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tumoral calcinosis, hyperphosphatemic, familial, 3 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: 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	-0.92
CADD	Benign	0.0020
DANN	Benign	0.51
PhyloP100		-2.0
Mutation Taster		=15/85	disease causing

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: rs650439; hg19: chr13-33635939; COSMIC: COSV66308242;