chr10-101770378-G-A

Position:

chr10-101770378-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_033163.5(FGF8):c.686C>T(p.Thr229Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,603,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

FGF8
NM_033163.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.80

Variant links:

Genes affected

FGF8 (HGNC:3686): (fibroblast growth factor 8) 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. This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogensis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs revealed roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]

FGF8 links:

LOC105378457 (HGNC:):

LOC105378457 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050103843).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000177 (27/152312) while in subpopulation SAS AF= 0.00207 (10/4826). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 27 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF8	NM_033163.5 linkuse as main transcript	c.686C>T	p.Thr229Met	missense_variant	6/6	ENST00000320185.7
LOC105378457	XR_007062268.1 linkuse as main transcript	n.138-179G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF8	ENST00000320185.7 linkuse as main transcript	c.686C>T	p.Thr229Met	missense_variant	6/6	1	NM_033163.5	A2	P55075-4

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000260

AC:

AN:

226744

Hom.:

AF XY:

0.000284

AC XY:

AN XY:

123146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000891

Gnomad SAS exome

AF:

0.00129

Gnomad FIN exome

AF:

0.000105

Gnomad NFE exome

AF:

0.0000393

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.000159

AC:

231

AN:

1451094

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

126

AN XY:

720990

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000535

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.000134

Gnomad4 NFE exome

AF:

0.0000686

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.000177

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000248

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	FGF8: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a possible damaging effect on protein function, but the biological significance of the findings is not established (Falardeau et al., 2008); This variant is associated with the following publications: (PMID: 21664428, 21976454, 21045958, 19621416, 28645738, 18596921) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 229 of the FGF8 protein (p.Thr229Met). This variant is present in population databases (rs137852664, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with idiopathic hypogonadotropic hypogonadism (PMID: 18596921). ClinVar contains an entry for this variant (Variation ID: 9126). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hypogonadotropic hypogonadism 6 with or without anosmia

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

Holoprosencephaly 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;D;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.050

T;T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.0

.;N;.;.;.

MutationTaster

Benign

0.86

N;N;N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.3

.;N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.052

.;T;D;D;T

Sift4G

Uncertain

0.018

D;D;D;D;D

Polyphen

0.99, 1.0, 1.0

.;D;D;D;D

Vest4

0.36

MVP

0.87

MPC

1.8

ClinPred

0.099

GERP RS

3.8

Varity_R

0.079

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over