13-33024849-A-G

Variant names:

• chr13-33024849-A-G
• rs526906
• NM_004795.4:c.819+7590A>G

Variant summary

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

The ENST00000380099.4(KL):​c.819+7590A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 152,002 control chromosomes in the GnomAD database, including 43,347 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 0.74 (43347 hom., cov: 32)
• Consequence: KL ENST00000380099.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• Publications: 13 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380099.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	NM_004795.4	MANE Select	c.819+7590A>G		intron	N/A	NP_004786.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.819+7590A>G		intron	N/A	ENSP00000369442.3
	KL	ENST00000487852.1	TSL:5	n.827+7590A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112064 AN: 151884 Hom.: 43333 Cov.: 32

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.895

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.777

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

GnomAD4 genome AF: 0.738 AC: 112116 AN: 152002 Hom.: 43347 Cov.: 32 AF XY: 0.741 AC XY: 55066 AN XY: 74330

African (AFR) AF: 0.490 AC: 20288 AN: 41426

American (AMR) AF: 0.765 AC: 11675 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 3111 AN: 3470

East Asian (EAS) AF: 0.638 AC: 3264 AN: 5116

South Asian (SAS) AF: 0.802 AC: 3860 AN: 4814

European-Finnish (FIN) AF: 0.895 AC: 9486 AN: 10604

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.849 AC: 57710 AN: 67990

Other (OTH) AF: 0.777 AC: 1639 AN: 2110

Alfa AF: 0.796 Hom.: 102968

Bravo AF: 0.718

Asia WGS AF: 0.710 AC: 2472 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.29
PhyloP100		-0.41
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: rs526906; hg19: chr13-33598987;