NM_033163.5:c.77C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033163.5(FGF8):c.77C>T(p.Pro26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,539,758 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00084 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

FGF8
NM_033163.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:2O:1

Conservation

PhyloP100: 0.854

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06352016).

BP6

Variant 10-101775209-G-A is Benign according to our data. Variant chr10-101775209-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9122.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=1, not_provided=1}. Variant chr10-101775209-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000843 (128/151926) while in subpopulation SAS AF= 0.00145 (7/4830). AF 95% confidence interval is 0.00115. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 128 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF8	NM_033163.5 link	c.77C>T	p.Pro26Leu	missense_variant	Exon 3 of 6	ENST00000320185.7	NP_149353.1	P55075-4A1A515

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF8	ENST00000320185.7 link	c.77C>T	p.Pro26Leu	missense_variant	Exon 3 of 6	1	NM_033163.5	ENSP00000321797.2		P55075-4

Frequencies

GnomAD3 genomes

AF:

0.000843

AC:

128

AN:

151808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00115

AC:

167

AN:

145328

Hom.:

AF XY:

0.00111

AC XY:

AN XY:

78512

show subpopulations

Gnomad AFR exome

AF:

0.000150

Gnomad AMR exome

AF:

0.000408

Gnomad ASJ exome

AF:

0.00523

Gnomad EAS exome

AF:

0.0000934

Gnomad SAS exome

AF:

0.00106

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.000718

GnomAD4 exome

AF:

0.00107

AC:

1484

AN:

1387832

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

758

AN XY:

684482

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

Gnomad4 AMR exome

AF:

0.000532

Gnomad4 ASJ exome

AF:

0.00576

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00121

Gnomad4 FIN exome

AF:

0.000890

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.00135

GnomAD4 genome

AF:

0.000843

AC:

128

AN:

151926

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000689

AC:

ExAC

AF:

0.000584

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 6 with or without anosmia

Pathogenic:1Uncertain:2Other:1

Aug 05, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 10-23-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Aug 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:2

Apr 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with VATER/VACTERL-like phenotype and the unaffected father and paternal grandfather in published literature (Zeidler et al., 2014); Published functional in vitro studies demonstrate that the variant results in a significant reduction in reporter activity compared to wild-type; the senior author has suggested it could act as a modifier locus (Falardeau et al., 2008; N. Pitteloud, personal communication); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20463092, 21506104, 21045958, 27899157, 30669598, 20696889, 23643382, 25131394, 29419413, 28754744, 29165578, 28387797, 18596921, 34198905, 36842078) -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGF8: BS1 -

not specified

Uncertain:1

Jul 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Uncertain

0.51

D;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.7

L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.45

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.40

T;T

Sift4G

Uncertain

0.030

D;D

Polyphen

0.0010

B;B

Vest4

0.48

MVP

0.94

MPC

0.85

ClinPred

0.012

GERP RS

-0.41

Varity_R

0.047

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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