13-33025521-A-G

Variant names:

• chr13-33025521-A-G
• rs565587
• NM_004795.4:c.819+8262A>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+8262A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 152,006 control chromosomes in the GnomAD database, including 28,293 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 0.59 (28293 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.615
• 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: 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.819+8262A>G		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-103+9208A>G		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.819+8262A>G		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.819+8262A>G		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.819+8262A>G		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.827+8262A>G		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89562 AN: 151888 Hom.: 28284 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.635

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

GnomAD4 genome AF: 0.589 AC: 89598 AN: 152006 Hom.: 28293 Cov.: 32 AF XY: 0.592 AC XY: 43967 AN XY: 74330

African (AFR) AF: 0.338 AC: 14007 AN: 41438

American (AMR) AF: 0.663 AC: 10139 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2286 AN: 3466

East Asian (EAS) AF: 0.634 AC: 3272 AN: 5158

South Asian (SAS) AF: 0.633 AC: 3044 AN: 4812

European-Finnish (FIN) AF: 0.701 AC: 7417 AN: 10576

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47155 AN: 67962

Other (OTH) AF: 0.635 AC: 1332 AN: 2096

Alfa AF: 0.583 Hom.: 4091

Bravo AF: 0.580

Asia WGS AF: 0.636 AC: 2213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.8
DANN	Benign	0.77
PhyloP100		-0.61
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: rs565587; hg19: chr13-33599659;