rs7323281

Variant names:

• chr13-33053623-A-G
• rs7323281
• NM_004795.4:c.820-144A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004795.4(KL):​c.820-144A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 774,990 control chromosomes in the GnomAD database, including 33,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5842 hom., cov: 33)
  • Exomes 𝑓: 0.30 (28122 hom.)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• Publications: 10 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-33053623-A-G is Benign according to our data. Variant chr13-33053623-A-G is described in ClinVar as Benign. ClinVar VariationId is 1233548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	NM_004795.4	MANE Select	c.820-144A>G		intron	N/A	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.820-144A>G		intron	N/A	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.828-144A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40403 AN: 151994 Hom.: 5838 Cov.: 33

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.295 AC: 183967 AN: 622880 Hom.: 28122 AF XY: 0.296 AC XY: 96030 AN XY: 324506

African (AFR) AF: 0.201 AC: 3316 AN: 16476

American (AMR) AF: 0.178 AC: 4798 AN: 26898

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 4166 AN: 15954

East Asian (EAS) AF: 0.462 AC: 15579 AN: 33728

South Asian (SAS) AF: 0.301 AC: 15934 AN: 52934

European-Finnish (FIN) AF: 0.292 AC: 10152 AN: 34796

Middle Eastern (MID) AF: 0.269 AC: 971 AN: 3612

European-Non Finnish (NFE) AF: 0.295 AC: 119993 AN: 406322

Other (OTH) AF: 0.282 AC: 9058 AN: 32160

GnomAD4 genome AF: 0.266 AC: 40420 AN: 152110 Hom.: 5842 Cov.: 33 AF XY: 0.268 AC XY: 19904 AN XY: 74368

African (AFR) AF: 0.200 AC: 8292 AN: 41496

American (AMR) AF: 0.215 AC: 3287 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 902 AN: 3470

East Asian (EAS) AF: 0.451 AC: 2329 AN: 5160

South Asian (SAS) AF: 0.331 AC: 1599 AN: 4828

European-Finnish (FIN) AF: 0.306 AC: 3238 AN: 10576

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19769 AN: 67968

Other (OTH) AF: 0.283 AC: 598 AN: 2114

Alfa AF: 0.263 Hom.: 796

Bravo AF: 0.257

Asia WGS AF: 0.347 AC: 1206 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.9
DANN	Benign	0.54
PhyloP100		1.1
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: rs7323281; hg19: chr13-33627760;