rs1888057

Variant names:

• chr13-33048558-C-T
• rs1888057
• NM_004795.4:c.820-5209C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004795.4(KL):​c.820-5209C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,270 control chromosomes in the GnomAD database, including 2,866 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2866 hom., cov: 33)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.820-5209C>T		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-102-5209C>T		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.820-5209C>T		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.820-5209C>T		intron_variant	Intron 1 of 3		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.820-5209C>T		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.828-5209C>T		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28126 AN: 152152 Hom.: 2866 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.178

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.185 AC: 28122 AN: 152270 Hom.: 2866 Cov.: 33 AF XY: 0.187 AC XY: 13886 AN XY: 74446

African (AFR) AF: 0.110 AC: 4568 AN: 41578

American (AMR) AF: 0.149 AC: 2279 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 756 AN: 3472

East Asian (EAS) AF: 0.296 AC: 1535 AN: 5178

South Asian (SAS) AF: 0.280 AC: 1352 AN: 4832

European-Finnish (FIN) AF: 0.213 AC: 2253 AN: 10582

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14790 AN: 68012

Other (OTH) AF: 0.178 AC: 377 AN: 2116

Alfa AF: 0.207 Hom.: 2481

Bravo AF: 0.170

Asia WGS AF: 0.259 AC: 898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.79
PhyloP100		0.32
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: rs1888057; hg19: chr13-33622695; COSMIC: COSV66309895;