rs9596717

Variant names:

• chr13-33057870-A-G
• rs9596717
• NM_004795.4:c.1599+2555A>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.1599+2555A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0684 in 152,244 control chromosomes in the GnomAD database, including 361 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 0.068 (361 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0840
• Publications: 0 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 (NFE) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.1599+2555A>G		intron_variant	Intron 3 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.678+2555A>G		intron_variant	Intron 3 of 4		XP_006719958.1
KL	XM_047430775.1	c.1650-78A>G		intron_variant	Intron 3 of 3		XP_047286731.1
KL	XM_047430776.1	c.1649+2505A>G		intron_variant	Intron 3 of 3		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.1599+2555A>G		intron_variant	Intron 3 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.1657+2505A>G		intron_variant	Intron 3 of 4	5

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 10397 AN: 152126 Hom.: 359 Cov.: 32

Gnomad AFR AF: 0.0572

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0541

Gnomad ASJ AF: 0.0856

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0818

Gnomad OTH AF: 0.0731

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

GnomAD4 genome AF: 0.0684 AC: 10411 AN: 152244 Hom.: 361 Cov.: 32 AF XY: 0.0681 AC XY: 5071 AN XY: 74428

African (AFR) AF: 0.0573 AC: 2380 AN: 41550

American (AMR) AF: 0.0538 AC: 823 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 297 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0558 AC: 269 AN: 4818

European-Finnish (FIN) AF: 0.0814 AC: 863 AN: 10604

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0818 AC: 5562 AN: 68008

Other (OTH) AF: 0.0723 AC: 153 AN: 2116

Alfa AF: 0.0710 Hom.: 61

Bravo AF: 0.0658

Asia WGS AF: 0.0310 AC: 112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.89
DANN	Benign	0.77
PhyloP100		-0.084
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: rs9596717; hg19: chr13-33632007;