13-33017932-A-G

Variant names:

• chr13-33017932-A-G
• rs562020
• NM_004795.4:c.819+673A>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.819+673A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 152,156 control chromosomes in the GnomAD database, including 36,142 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 0.69 (36142 hom., cov: 33)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.493
• Publications: 17 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.819+673A>G		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-103+1619A>G		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.819+673A>G		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.819+673A>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.819+673A>G		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.827+673A>G		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104183 AN: 152038 Hom.: 36096 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.786

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.660

Gnomad OTH AF: 0.681

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

GnomAD4 genome AF: 0.685 AC: 104280 AN: 152156 Hom.: 36142 Cov.: 33 AF XY: 0.684 AC XY: 50828 AN XY: 74364

African (AFR) AF: 0.782 AC: 32452 AN: 41522

American (AMR) AF: 0.555 AC: 8479 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2166 AN: 3470

East Asian (EAS) AF: 0.786 AC: 4072 AN: 5180

South Asian (SAS) AF: 0.723 AC: 3493 AN: 4828

European-Finnish (FIN) AF: 0.614 AC: 6478 AN: 10558

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.660 AC: 44860 AN: 67990

Other (OTH) AF: 0.680 AC: 1438 AN: 2116

Alfa AF: 0.666 Hom.: 94872

Bravo AF: 0.678

Asia WGS AF: 0.705 AC: 2453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.55
PhyloP100		-0.49
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: rs562020; hg19: chr13-33592070;