13-33026409-A-T

Variant names:

• chr13-33026409-A-T
• rs580332
• NM_004795.4:c.819+9150A>T

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+9150A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,404 control chromosomes in the GnomAD database, including 8,694 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 0.31 (8694 hom., cov: 31)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 2 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 (AMR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.819+9150A>T		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-103+10096A>T		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.819+9150A>T		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.819+9150A>T		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+9150A>T		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.827+9150A>T		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47475 AN: 151286 Hom.: 8684 Cov.: 31

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.314 AC: 47504 AN: 151404 Hom.: 8694 Cov.: 31 AF XY: 0.313 AC XY: 23148 AN XY: 73930

African (AFR) AF: 0.138 AC: 5691 AN: 41274

American (AMR) AF: 0.437 AC: 6645 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1292 AN: 3466

East Asian (EAS) AF: 0.162 AC: 825 AN: 5108

South Asian (SAS) AF: 0.244 AC: 1157 AN: 4736

European-Finnish (FIN) AF: 0.381 AC: 3986 AN: 10456

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

European-Non Finnish (NFE) AF: 0.394 AC: 26711 AN: 67862

Other (OTH) AF: 0.346 AC: 727 AN: 2102

Alfa AF: 0.336 Hom.: 1199

Bravo AF: 0.313

Asia WGS AF: 0.256 AC: 891 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	7.6
DANN	Benign	0.72
PhyloP100		1.3
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: rs580332; hg19: chr13-33600547;