rs764384920

Variant names:

• chr4-39407292-C-T
• rs764384920
• NM_175737.4:c.343C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_175737.4(KLB):​c.343C>T​(p.His115Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,762 control chromosomes in the GnomAD database, including 1 homozygotes. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (1 hom.)
• Consequence: KLB NM_175737.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16
• Publications: 0 publications found

Genes affected

KLB (HGNC:15527): (klotho beta) Enables fibroblast growth factor binding activity and fibroblast growth factor receptor binding activity. Predicted to be involved in fibroblast growth factor receptor signaling pathway. Predicted to act upstream of or within positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway and positive regulation of cell population proliferation. Predicted to be located in plasma membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175737.4. 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
	KLB	NM_175737.4	MANE Select	c.343C>T	p.His115Tyr	missense	Exon 1 of 5	NP_783864.1	Q86Z14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLB	ENST00000257408.5	TSL:1 MANE Select	c.343C>T	p.His115Tyr	missense	Exon 1 of 5	ENSP00000257408.4	Q86Z14
	KLB	ENST00000859482.1		c.343C>T	p.His115Tyr	missense	Exon 1 of 5	ENSP00000529541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251356 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461762 Hom.: 1 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727182

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111902

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.92
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.2
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.089
Sift	Benign	0.041	D
Sift4G	Benign	0.076	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.81		Loss of disorder (P = 0.0412)
MVP		0.41
MPC		0.70
ClinPred		0.17	T
GERP RS		-1.9
PromoterAI		-0.0050	Neutral
Varity_R		0.24
gMVP		0.76
Mutation Taster		=89/11	polymorphism

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: rs764384920; hg19: chr4-39408912;