NM_004795.4:c.820-5087G>A

Variant names:

• chr13-33048680-G-A
• rs657049
• NM_004795.4:c.820-5087G>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.820-5087G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 151,964 control chromosomes in the GnomAD database, including 34,137 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 0.67 (34137 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0970
• Publications: 9 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004795.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	NM_004795.4	MANE Select	c.820-5087G>A		intron	N/A	NP_004786.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.820-5087G>A		intron	N/A	ENSP00000369442.3
	KL	ENST00000487852.1	TSL:5	n.828-5087G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101053 AN: 151846 Hom.: 34097 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.693

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

GnomAD4 genome AF: 0.666 AC: 101144 AN: 151964 Hom.: 34137 Cov.: 32 AF XY: 0.667 AC XY: 49550 AN XY: 74264

African (AFR) AF: 0.552 AC: 22865 AN: 41402

American (AMR) AF: 0.763 AC: 11670 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2401 AN: 3470

East Asian (EAS) AF: 0.704 AC: 3633 AN: 5164

South Asian (SAS) AF: 0.658 AC: 3171 AN: 4816

European-Finnish (FIN) AF: 0.706 AC: 7442 AN: 10546

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47578 AN: 67964

Other (OTH) AF: 0.694 AC: 1464 AN: 2108

Alfa AF: 0.696 Hom.: 51188

Bravo AF: 0.670

Asia WGS AF: 0.691 AC: 2403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.6
DANN	Benign	0.45
PhyloP100		-0.097
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: rs657049; hg19: chr13-33622817;