NM_004795.4:c.819+8880T>C

Variant names:

• chr13-33026139-T-C
• rs516306
• NM_004795.4:c.819+8880T>C

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+8880T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 152,012 control chromosomes in the GnomAD database, including 8,799 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 (8799 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 8 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.429 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.819+8880T>C		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.819+8880T>C		intron	N/A	ENSP00000369442.3
	KL	ENST00000487852.1	TSL:5	n.827+8880T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47960 AN: 151894 Hom.: 8789 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.338

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

GnomAD4 genome AF: 0.316 AC: 47987 AN: 152012 Hom.: 8799 Cov.: 32 AF XY: 0.315 AC XY: 23388 AN XY: 74318

African (AFR) AF: 0.145 AC: 6006 AN: 41438

American (AMR) AF: 0.437 AC: 6682 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1293 AN: 3472

East Asian (EAS) AF: 0.175 AC: 905 AN: 5182

South Asian (SAS) AF: 0.241 AC: 1161 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 4024 AN: 10578

Middle Eastern (MID) AF: 0.424 AC: 123 AN: 290

European-Non Finnish (NFE) AF: 0.393 AC: 26725 AN: 67932

Other (OTH) AF: 0.342 AC: 723 AN: 2116

Alfa AF: 0.330 Hom.: 1751

Bravo AF: 0.316

Asia WGS AF: 0.260 AC: 905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.55
DANN	Benign	0.45
PhyloP100		-1.4
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: rs516306; hg19: chr13-33600277;