rs576404

Variant names:

• chr13-33018962-C-A
• rs576404
• NM_004795.4:c.819+1703C>A

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+1703C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 151,960 control chromosomes in the GnomAD database, including 9,230 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 0.32 (9230 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• Publications: 11 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.819+1703C>A		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-103+2649C>A		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.819+1703C>A		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.819+1703C>A		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+1703C>A		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.827+1703C>A		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48947 AN: 151842 Hom.: 9223 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.353

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

GnomAD4 genome AF: 0.322 AC: 48963 AN: 151960 Hom.: 9230 Cov.: 32 AF XY: 0.322 AC XY: 23882 AN XY: 74272

African (AFR) AF: 0.137 AC: 5694 AN: 41468

American (AMR) AF: 0.441 AC: 6725 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1330 AN: 3466

East Asian (EAS) AF: 0.161 AC: 832 AN: 5180

South Asian (SAS) AF: 0.269 AC: 1300 AN: 4826

European-Finnish (FIN) AF: 0.402 AC: 4230 AN: 10514

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27635 AN: 67944

Other (OTH) AF: 0.355 AC: 747 AN: 2106

Alfa AF: 0.360 Hom.: 1487

Bravo AF: 0.320

Asia WGS AF: 0.262 AC: 913 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.1
DANN	Benign	0.66
PhyloP100		0.31
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: rs576404; hg19: chr13-33593100;