13-33020018-A-G

Variant names:

• chr13-33020018-A-G
• rs499091
• NM_004795.4:c.819+2759A>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.819+2759A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,010 control chromosomes in the GnomAD database, including 9,503 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 0.33 (9503 hom., cov: 31)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.44 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.819+2759A>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.819+2759A>G		intron	N/A	ENSP00000369442.3
	KL	ENST00000487852.1	TSL:5	n.827+2759A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49997 AN: 151892 Hom.: 9493 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.329 AC: 50019 AN: 152010 Hom.: 9503 Cov.: 31 AF XY: 0.328 AC XY: 24396 AN XY: 74314

African (AFR) AF: 0.152 AC: 6329 AN: 41502

American (AMR) AF: 0.449 AC: 6847 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1344 AN: 3470

East Asian (EAS) AF: 0.160 AC: 829 AN: 5166

South Asian (SAS) AF: 0.270 AC: 1301 AN: 4810

European-Finnish (FIN) AF: 0.405 AC: 4275 AN: 10548

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

European-Non Finnish (NFE) AF: 0.410 AC: 27857 AN: 67938

Other (OTH) AF: 0.363 AC: 766 AN: 2108

Alfa AF: 0.378 Hom.: 14477

Bravo AF: 0.328

Asia WGS AF: 0.267 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.34
DANN	Benign	0.75
PhyloP100		-0.26
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: rs499091; hg19: chr13-33594156;