4-39407182-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_175737.4(KLB):c.233A>G(p.Tyr78Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KLB NM_175737.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLB	NM_175737.4	c.233A>G	p.Tyr78Cys	missense_variant	1/5	ENST00000257408.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLB	ENST00000257408.5	c.233A>G	p.Tyr78Cys	missense_variant	1/5	1	NM_175737.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KLB protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with KLB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 78 of the KLB protein (p.Tyr78Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.74
MutPred		0.56		Gain of catalytic residue at T80 (P = 0.0763);
MVP		0.61
MPC		1.6
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.57
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-39408802;