rs553791

Variant names:

• chr13-33050343-T-G
• rs553791
• NM_004795.4:c.820-3424T>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.820-3424T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 152,060 control chromosomes in the GnomAD database, including 34,119 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 (34119 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• Publications: 3 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.820-3424T>G		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-102-3424T>G		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.820-3424T>G		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.820-3424T>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.820-3424T>G		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.828-3424T>G		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.665 AC: 101039 AN: 151942 Hom.: 34079 Cov.: 32

Gnomad AFR AF: 0.551

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: 0.705

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: 0.665 AC: 101130 AN: 152060 Hom.: 34119 Cov.: 32 AF XY: 0.667 AC XY: 49540 AN XY: 74320

African (AFR) AF: 0.551 AC: 22834 AN: 41438

American (AMR) AF: 0.763 AC: 11659 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2403 AN: 3472

East Asian (EAS) AF: 0.704 AC: 3645 AN: 5180

South Asian (SAS) AF: 0.658 AC: 3176 AN: 4824

European-Finnish (FIN) AF: 0.705 AC: 7447 AN: 10566

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

European-Non Finnish (NFE) AF: 0.700 AC: 47576 AN: 67982

Other (OTH) AF: 0.695 AC: 1470 AN: 2116

Alfa AF: 0.688 Hom.: 6152

Bravo AF: 0.670

Asia WGS AF: 0.691 AC: 2403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.6
DANN	Benign	0.61
PhyloP100		-0.095
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: rs553791; hg19: chr13-33624480;