chr19-640097-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020637.2(FGF22):c.172G>C(p.Gly58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,399,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

FGF22
NM_020637.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.570

Publications

0 publications found

Variant links:

Genes affected

FGF22 (HGNC:3679): (fibroblast growth factor 22) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. The mouse homolog of this gene was found to be preferentially expressed in the inner root sheath of the hair follicle, which suggested a role in hair development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

FGF22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1590999).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF22	NM_020637.2 link	c.172G>C	p.Gly58Arg	missense_variant	Exon 1 of 3	ENST00000215530.7	NP_065688.1	Q9HCT0A0A7U3JVZ9
FGF22	NM_001300812.3 link	c.172G>C	p.Gly58Arg	missense_variant	Exon 1 of 3		NP_001287741.1	K7ELB9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGF22	ENST00000215530.7 link	c.172G>C	p.Gly58Arg	missense_variant	Exon 1 of 3	1	NM_020637.2	ENSP00000215530.4	Q9HCT0
FGF22	ENST00000586042.6 link	c.172G>C	p.Gly58Arg	missense_variant	Exon 1 of 3	1		ENSP00000466004.1	K7ELB9
FGF22	ENST00000591390.1 link	n.219G>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1247330

Hom.:

Cov.:

AF XY:

0.0000244

AC XY:

AN XY:

614210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25330

American (AMR)

AF:

0.00

AC:

AN:

19926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20890

East Asian (EAS)

AF:

0.00

AC:

AN:

27734

South Asian (SAS)

AF:

0.00

AC:

AN:

60842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30116

Middle Eastern (MID)

AF:

0.000280

AC:

AN:

3572

European-Non Finnish (NFE)

AF:

0.0000218

AC:

AN:

1008304

Other (OTH)

AF:

0.00

AC:

AN:

50616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.172G>C (p.G58R) alteration is located in exon 1 (coding exon 1) of the FGF22 gene. This alteration results from a G to C substitution at nucleotide position 172, causing the glycine (G) at amino acid position 58 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.37

CADD

Benign

2.0

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.40

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.37

T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.86

.;L

PhyloP100

-0.57

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.58

.;N

REVEL

Benign

0.14

Sift

Benign

0.46

.;T

Sift4G

Benign

0.44

T;T

Polyphen

0.015

.;B

Vest4

0.14

MutPred

0.58

Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);

MVP

0.48

MPC

0.010

ClinPred

0.042

GERP RS

-4.3

PromoterAI

0.018

Neutral

(source)

Varity_R

0.047

gMVP

0.33

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over