rs137852660

Positions:

• chr10-101775209-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: FGF8 NM_033163.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:2 O:1
• Conservation: PhyloP100: 0.854

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]

ACMG classification

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: {not_provided=1, Likely_benign=1, Uncertain_significance=3, Benign=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/exons	MANE	UniProt
FGF8	NM_033163.5	c.77C>T	p.Pro26Leu	missense_variant	3/6	ENST00000320185.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF8	ENST00000320185.7	c.77C>T	p.Pro26Leu	missense_variant	3/6	1	NM_033163.5	A2

Frequencies

GnomAD3 genomes AF: 0.000843 AC: 128 AN: 151808 Hom.: 1 Cov.: 31

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.: 0 AF XY: 0.00111 AC XY: 87 AN XY: 78512

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.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 758 AN XY: 684482

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.: 1 Cov.: 31 AF XY: 0.000713 AC XY: 53 AN XY: 74304

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.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000689 AC: 5

ExAC AF: 0.000584 AC: 37

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 6 with or without anosmia Pathogenic:1 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 05, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2008	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2023	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	FGF8: BS1 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	6.1e-9	A;A;A;A
PrimateAI	Uncertain	0.75	T
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	T
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

Other links and lift over

dbSNP: rs137852660; hg19: chr10-103534966;