rs649964

Positions:

• chr13-33061698-T-A
• chr13-33061698-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004795.4(KL):​c.2619T>A​(p.Asn873Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N873N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KL NM_004795.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KL	NM_004795.4	c.2619T>A	p.Asn873Lys	missense_variant	4/5	ENST00000380099.4	NP_004786.2
KL	XM_006719895.3	c.1698T>A	p.Asn566Lys	missense_variant	4/5		XP_006719958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4	c.2619T>A	p.Asn873Lys	missense_variant	4/5	1	NM_004795.4	ENSP00000369442.3
KL	ENST00000487852.1	n.2677T>A		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251402 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461738 Hom.: 0 Cov.: 55 AF XY: 0.00000413 AC XY: 3 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	4.6	H
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.78		Gain of catalytic residue at N873 (P = 0);
MVP		0.80
MPC		0.60
ClinPred		1.0	D
GERP RS		-4.1
Varity_R		0.98
gMVP		0.98

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: rs649964; hg19: chr13-33635835;