4-39407142-C-G

Variant names:

• chr4-39407142-C-G
• rs34905034
• NM_175737.4:c.193C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01
• Publications: 8 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: Benign. The variant received -20 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 VariationId is 713092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.193C>G	p.Pro65Ala	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.193C>G	p.Pro65Ala	missense	Exon 1 of 5	ENSP00000257408.4	Q86Z14
	KLB	ENST00000859482.1		c.193C>G	p.Pro65Ala	missense	Exon 1 of 5	ENSP00000529541.1

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

GnomAD2 exomes AF: 0.00374 AC: 940 AN: 251434 AF XY: 0.00308

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 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

African (AFR) AF: 0.0227 AC: 759 AN: 33478

American (AMR) AF: 0.00470 AC: 210 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26136

East Asian (EAS) AF: 0.00751 AC: 298 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.000766 AC: 852 AN: 1111988

Other (OTH) AF: 0.00464 AC: 280 AN: 60394

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

African (AFR) AF: 0.0232 AC: 964 AN: 41544

American (AMR) AF: 0.00576 AC: 88 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68008

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.0
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
PromoterAI		0.012	Neutral
Varity_R		0.043
gMVP		0.50
Mutation Taster		=96/4	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: rs34905034; hg19: chr4-39408762;