Genetic Variant FGF22:p.Gly58Cys (chr19-640097-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_020637.2(FGF22):c.172G>T(p.Gly58Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000401 in 1,247,330 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

FGF22
NM_020637.2 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32247883).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF22	NM_020637.2 link	c.172G>T	p.Gly58Cys	missense_variant	Exon 1 of 3	ENST00000215530.7	NP_065688.1	Q9HCT0A0A7U3JVZ9
FGF22	NM_001300812.3 link	c.172G>T	p.Gly58Cys	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>T	p.Gly58Cys	missense_variant	Exon 1 of 3	1	NM_020637.2	ENSP00000215530.4	Q9HCT0
FGF22	ENST00000586042.6 link	c.172G>T	p.Gly58Cys	missense_variant	Exon 1 of 3	1		ENSP00000466004.1	K7ELB9
FGF22	ENST00000591390.1 link	n.219G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

59684

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000401

AC:

AN:

1247330

Hom.:

Cov.:

AF XY:

0.00000326

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:

0.00

AC:

AN:

3572

European-Non Finnish (NFE)

AF:

0.00000496

AC:

AN:

1008304

Other (OTH)

AF:

0.00

AC:

AN:

50616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.61

.;D

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.9

.;L

PhyloP100

-0.57

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.7

.;N

REVEL

Benign

0.22

Sift

Benign

0.044

.;D

Sift4G

Uncertain

0.033

D;T

Polyphen

0.13

.;B

Vest4

0.25

MutPred

0.60

Gain of catalytic residue at P57 (P = 0.0118);Gain of catalytic residue at P57 (P = 0.0118);

MVP

0.58

MPC

0.012

ClinPred

0.21

GERP RS

-4.3

PromoterAI

0.0075

Neutral

(source)

Varity_R

0.14

gMVP

0.40

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over