4-39407142-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_175737.4(KLB):c.193C>G(p.Pro65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,614,098 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (23 hom.)
• Consequence: KLB NM_175737.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.01

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002829045).
• BP6: Variant 4-39407142-C-G is Benign according to our data. Variant chr4-39407142-C-G is described in ClinVar as [Benign]. Clinvar id is 713092.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00782 (1191/152240) while in subpopulation AFR AF= 0.0232 (964/41544). AF 95% confidence interval is 0.022. There are 10 homozygotes in gnomad4. There are 533 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLB	NM_175737.4	c.193C>G	p.Pro65Ala	missense_variant	1/5	ENST00000257408.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLB	ENST00000257408.5	c.193C>G	p.Pro65Ala	missense_variant	1/5	1	NM_175737.4	P1

Frequencies

GnomAD3 genomes AF: 0.00778 AC: 1183 AN: 152122 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00374 AC: 940 AN: 251434 Hom.: 7 AF XY: 0.00308 AC XY: 419 AN XY: 135892

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000906

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00172 AC: 2514 AN: 1461858 Hom.: 23 Cov.: 32 AF XY: 0.00163 AC XY: 1188 AN XY: 727232

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.00470

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00751

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000766

Gnomad4 OTH exome AF: 0.00464

GnomAD4 genome AF: 0.00782 AC: 1191 AN: 152240 Hom.: 10 Cov.: 32 AF XY: 0.00716 AC XY: 533 AN XY: 74440

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0118

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00880

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00396 AC: 481

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	12
Dann	Benign	0.69
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.093
Sift	Benign	0.46	T
Sift4G	Benign	1.0	T
Polyphen		0.024	B
Vest4		0.15
MVP		0.35
MPC		0.57
ClinPred		0.0029	T
GERP RS		4.2
Varity_R		0.043
gMVP		0.50

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: rs34905034; hg19: chr4-39408762;