NM_004795.4:c.820-10730T>G

Variant names:

• chr13-33043037-T-G
• rs2320762
• NM_004795.4:c.820-10730T>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.820-10730T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 152,016 control chromosomes in the GnomAD database, including 9,905 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 0.35 (9905 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.547
• Publications: 12 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.820-10730T>G		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-102-10730T>G		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.820-10730T>G		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.820-10730T>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.820-10730T>G		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.828-10730T>G		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53512 AN: 151898 Hom.: 9903 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.352 AC: 53535 AN: 152016 Hom.: 9905 Cov.: 32 AF XY: 0.355 AC XY: 26390 AN XY: 74292

African (AFR) AF: 0.282 AC: 11677 AN: 41472

American (AMR) AF: 0.276 AC: 4223 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1308 AN: 3470

East Asian (EAS) AF: 0.509 AC: 2631 AN: 5164

South Asian (SAS) AF: 0.457 AC: 2198 AN: 4810

European-Finnish (FIN) AF: 0.403 AC: 4248 AN: 10542

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25938 AN: 67954

Other (OTH) AF: 0.368 AC: 776 AN: 2106

Alfa AF: 0.369 Hom.: 14626

Bravo AF: 0.340

Asia WGS AF: 0.417 AC: 1451 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2320762; hg19: chr13-33617174;