NM_004795.4:c.140G>T

Variant names:

• chr13-33016580-G-T
• rs201936594
• NM_004795.4:c.140G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004795.4(KL):​c.140G>T​(p.Arg47Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: KL NM_004795.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.403

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]

LOC124903151 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09306404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 5	ENST00000380099.4	NP_004786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.140G>T	p.Arg47Leu	missense_variant	Exon 1 of 5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.148G>T		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000117 AC: 1 AN: 85548 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 46406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000148

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1331938 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 651940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000300

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.1
DANN	Benign	0.67
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.031
Sift	Benign	0.42	T
Sift4G	Benign	0.71	T
Polyphen		0.11	B
Vest4		0.21
MutPred		0.47		Gain of catalytic residue at P48 (P = 0.001);
MVP		0.41
MPC		1.2
ClinPred		0.079	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs201936594; hg19: chr13-33590718;