19-640097-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_020637.2(FGF22):c.172G>A(p.Gly58Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,464 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 Likely benign (★). 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

FGF22
NM_020637.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B: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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.108605236).

BP6

Variant 19-640097-G-A is Benign according to our data. Variant chr19-640097-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3278638.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF22	NM_020637.2 link	c.172G>A	p.Gly58Ser	missense_variant	Exon 1 of 3	ENST00000215530.7	NP_065688.1	Q9HCT0A0A7U3JVZ9
FGF22	NM_001300812.3 link	c.172G>A	p.Gly58Ser	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>A	p.Gly58Ser	missense_variant	Exon 1 of 3	1	NM_020637.2	ENSP00000215530.4	Q9HCT0
FGF22	ENST00000586042.6 link	c.172G>A	p.Gly58Ser	missense_variant	Exon 1 of 3	1		ENSP00000466004.1	K7ELB9
FGF22	ENST00000591390.1 link	n.219G>A		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:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.02e-7

AC:

AN:

1247326

Hom.:

Cov.:

AF XY:

0.00000163

AC XY:

AN XY:

614208

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:

60840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3572

European-Non Finnish (NFE)

AF:

9.92e-7

AC:

AN:

1008302

Other (OTH)

AF:

0.00

AC:

AN:

50616

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.0000654

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:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 31, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.25

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.36

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.45

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.32

.;N

PhyloP100

-0.57

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.67

.;N

REVEL

Benign

0.12

Sift

Benign

0.49

.;T

Sift4G

Benign

0.98

T;T

Polyphen

0.025

.;B

Vest4

0.10

MutPred

0.48

Gain of glycosylation at G58 (P = 0.0295);Gain of glycosylation at G58 (P = 0.0295);

MVP

0.48

MPC

0.010

ClinPred

0.057

GERP RS

-4.3

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.061

gMVP

0.23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over