NM_004795.4:c.820-17193T>C

Variant names:

• chr13-33036574-T-C
• rs7982726
• NM_004795.4:c.820-17193T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004795.4(KL):​c.820-17193T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,016 control chromosomes in the GnomAD database, including 2,488 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 0.17 (2488 hom., cov: 32)
• Consequence: KL NM_004795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• Publications: 9 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=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.820-17193T>C		intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.-102-17193T>C		intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1	c.820-17193T>C		intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1	c.820-17193T>C		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.820-17193T>C		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.828-17193T>C		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26459 AN: 151896 Hom.: 2481 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.174 AC: 26484 AN: 152016 Hom.: 2488 Cov.: 32 AF XY: 0.173 AC XY: 12880 AN XY: 74304

African (AFR) AF: 0.244 AC: 10114 AN: 41444

American (AMR) AF: 0.115 AC: 1748 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 830 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5178

South Asian (SAS) AF: 0.170 AC: 817 AN: 4818

European-Finnish (FIN) AF: 0.192 AC: 2028 AN: 10572

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10471 AN: 67962

Other (OTH) AF: 0.157 AC: 332 AN: 2112

Alfa AF: 0.156 Hom.: 3305

Bravo AF: 0.169

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.3
DANN	Benign	0.88
PhyloP100		0.15
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: rs7982726; hg19: chr13-33610711;