rs577912

Variant names:

• chr13-33036014-T-G
• rs577912
• NM_004795.4:c.820-17753T>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.820-17753T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 152,130 control chromosomes in the GnomAD database, including 52,709 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 0.83 (52709 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394
• Publications: 21 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=-0.76).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.820-17753T>G		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-102-17753T>G		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.820-17753T>G		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.820-17753T>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.820-17753T>G		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.828-17753T>G		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126291 AN: 152012 Hom.: 52661 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.869

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.824

Gnomad FIN AF: 0.905

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.845

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

GnomAD4 genome AF: 0.831 AC: 126394 AN: 152130 Hom.: 52709 Cov.: 32 AF XY: 0.834 AC XY: 61996 AN XY: 74356

African (AFR) AF: 0.770 AC: 31943 AN: 41486

American (AMR) AF: 0.869 AC: 13289 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3152 AN: 3472

East Asian (EAS) AF: 0.723 AC: 3740 AN: 5170

South Asian (SAS) AF: 0.824 AC: 3968 AN: 4818

European-Finnish (FIN) AF: 0.905 AC: 9583 AN: 10592

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57840 AN: 67982

Other (OTH) AF: 0.844 AC: 1786 AN: 2116

Alfa AF: 0.838 Hom.: 17526

Bravo AF: 0.829

Asia WGS AF: 0.784 AC: 2727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.5
DANN	Benign	0.69
PhyloP100		0.39
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: rs577912; hg19: chr13-33610151;