13-33050208-A-G

Variant names:

• chr13-33050208-A-G
• rs684492
• NM_004795.4:c.820-3559A>G

Variant summary

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

The NM_004795.4(KL):​c.820-3559A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 152,094 control chromosomes in the GnomAD database, including 34,162 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 0.67 (34162 hom., cov: 33)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.752 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.820-3559A>G		intron	N/A	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.820-3559A>G		intron	N/A	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.828-3559A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101127 AN: 151974 Hom.: 34122 Cov.: 33

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.693

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

GnomAD4 genome AF: 0.665 AC: 101218 AN: 152094 Hom.: 34162 Cov.: 33 AF XY: 0.667 AC XY: 49606 AN XY: 74344

African (AFR) AF: 0.552 AC: 22859 AN: 41438

American (AMR) AF: 0.763 AC: 11671 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2401 AN: 3468

East Asian (EAS) AF: 0.705 AC: 3653 AN: 5182

South Asian (SAS) AF: 0.659 AC: 3175 AN: 4820

European-Finnish (FIN) AF: 0.706 AC: 7474 AN: 10584

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47595 AN: 67988

Other (OTH) AF: 0.695 AC: 1470 AN: 2116

Alfa AF: 0.685 Hom.: 6294

Bravo AF: 0.670

Asia WGS AF: 0.691 AC: 2402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.1
DANN	Benign	0.68
PhyloP100		-0.29
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: rs684492; hg19: chr13-33624345;