chr13-33016713-T-C

Variant names:

• chr13-33016713-T-C
• rs2772364
• NM_004795.4:c.273T>C

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.273T>C​(p.Asp91Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,610,264 control chromosomes in the GnomAD database, including 790,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68934 hom., cov: 31)
  • Exomes 𝑓: 0.99 (722053 hom.)
• Consequence: KL NM_004795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.04
• 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 13-33016713-T-C is Benign according to our data. Variant chr13-33016713-T-C is described in ClinVar as Benign. ClinVar VariationId is 311680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.273T>C	p.Asp91Asp	synonymous	Exon 1 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.273T>C	p.Asp91Asp	synonymous	Exon 1 of 5	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.281T>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.950 AC: 144198 AN: 151858 Hom.: 68894 Cov.: 31

Gnomad AFR AF: 0.825

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.968

GnomAD2 exomes AF: 0.988 AC: 231274 AN: 234070 AF XY: 0.991

Gnomad AFR exome AF: 0.824

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.995 AC: 1450643 AN: 1458290 Hom.: 722053 Cov.: 79 AF XY: 0.995 AC XY: 721940 AN XY: 725268

African (AFR) AF: 0.822 AC: 27452 AN: 33410

American (AMR) AF: 0.989 AC: 44086 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26009 AN: 26026

East Asian (EAS) AF: 1.00 AC: 39628 AN: 39628

South Asian (SAS) AF: 0.999 AC: 85698 AN: 85750

European-Finnish (FIN) AF: 1.00 AC: 51954 AN: 51954

Middle Eastern (MID) AF: 0.990 AC: 5708 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1110621 AN: 1110988

Other (OTH) AF: 0.988 AC: 59487 AN: 60214

GnomAD4 genome AF: 0.949 AC: 144291 AN: 151974 Hom.: 68934 Cov.: 31 AF XY: 0.951 AC XY: 70651 AN XY: 74304

African (AFR) AF: 0.825 AC: 34227 AN: 41478

American (AMR) AF: 0.979 AC: 14986 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3467 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5066 AN: 5066

South Asian (SAS) AF: 0.999 AC: 4820 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10590 AN: 10590

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67885 AN: 67924

Other (OTH) AF: 0.969 AC: 2050 AN: 2116

Alfa AF: 0.986 Hom.: 23970

Bravo AF: 0.941

Asia WGS AF: 0.989 AC: 3441 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Tumoral calcinosis, hyperphosphatemic, familial, 3 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		3.0
PromoterAI		-0.017	Neutral
Mutation Taster		=98/2	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: rs2772364; hg19: chr13-33590851; COSMIC: COSV66308010;