rs9527026

Variant names:

• chr13-33054102-G-A
• rs9527026
• NM_004795.4:c.1155G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004795.4(KL):​c.1155G>A​(p.Lys385Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,384 control chromosomes in the GnomAD database, including 20,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1939 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18478 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.370
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 13-33054102-G-A is Benign according to our data. Variant chr13-33054102-G-A is described in ClinVar as Benign. ClinVar VariationId is 311692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 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.1155G>A	p.Lys385Lys	synonymous	Exon 2 of 5	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.1155G>A	p.Lys385Lys	synonymous	Exon 2 of 5	ENSP00000369442.3
	KL	ENST00000487852.1	TSL:5	n.1163G>A		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23661 AN: 151758 Hom.: 1938 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.141 AC: 35481 AN: 251310 AF XY: 0.146

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0734

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.154 AC: 225453 AN: 1461508 Hom.: 18478 Cov.: 34 AF XY: 0.155 AC XY: 112659 AN XY: 727060

African (AFR) AF: 0.178 AC: 5964 AN: 33472

American (AMR) AF: 0.0770 AC: 3442 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5439 AN: 26128

East Asian (EAS) AF: 0.000856 AC: 34 AN: 39700

South Asian (SAS) AF: 0.174 AC: 15000 AN: 86240

European-Finnish (FIN) AF: 0.198 AC: 10553 AN: 53362

Middle Eastern (MID) AF: 0.163 AC: 937 AN: 5766

European-Non Finnish (NFE) AF: 0.157 AC: 174129 AN: 1111730

Other (OTH) AF: 0.165 AC: 9955 AN: 60386

GnomAD4 genome AF: 0.156 AC: 23674 AN: 151876 Hom.: 1939 Cov.: 32 AF XY: 0.157 AC XY: 11651 AN XY: 74208

African (AFR) AF: 0.183 AC: 7579 AN: 41392

American (AMR) AF: 0.103 AC: 1564 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 749 AN: 3472

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5168

South Asian (SAS) AF: 0.161 AC: 773 AN: 4796

European-Finnish (FIN) AF: 0.193 AC: 2032 AN: 10534

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10518 AN: 67952

Other (OTH) AF: 0.148 AC: 312 AN: 2106

Alfa AF: 0.155 Hom.: 1338

Bravo AF: 0.148

Asia WGS AF: 0.0750 AC: 264 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.155

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Tumoral calcinosis, hyperphosphatemic, familial, 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.54
PhyloP100		0.37
Mutation Taster		=79/21	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: rs9527026; hg19: chr13-33628239; COSMIC: COSV66309497;