rs137852660

Variant names:

• chr10-101775209-G-A
• rs137852660
• NM_033163.5:c.77C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-101775209-G-A
• chr10-101775209-G-C
• chr10-101775209-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

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. 14/22 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:4 B:2 O:1
• Conservation: PhyloP100: 0.854
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 6 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.5674 (below the threshold of 3.09). Trascript score misZ: 1.0113 (below the threshold of 3.09). GenCC associations: The gene is linked to hypogonadotropic hypogonadism, holoprosencephaly, hypogonadotropic hypogonadism 6 with or without anosmia, Kallmann syndrome.
• 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 submission is: [Conflicting_classifications_of_pathogenicity].
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

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

Ensembl

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

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

GnomAD2 exomes AF: 0.00115 AC: 167 AN: 145328 AF XY: 0.00111

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 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

African (AFR) AF: 0.000127 AC: 4 AN: 31502

American (AMR) AF: 0.000532 AC: 19 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 145 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35712

South Asian (SAS) AF: 0.00121 AC: 96 AN: 79152

European-Finnish (FIN) AF: 0.000890 AC: 42 AN: 47206

Middle Eastern (MID) AF: 0.000458 AC: 2 AN: 4366

European-Non Finnish (NFE) AF: 0.00102 AC: 1098 AN: 1071410

Other (OTH) AF: 0.00135 AC: 78 AN: 57648

GnomAD4 genome AF: 0.000843 AC: 128 AN: 151926 Hom.: 1 Cov.: 31 AF XY: 0.000713 AC XY: 53 AN XY: 74304

African (AFR) AF: 0.000120 AC: 5 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 67654

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00149 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:4 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 6 with or without anosmia Pathogenic:1 Uncertain:2 Other:1

Aug 05, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

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. -

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGF8: BS1 -

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

- -

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	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
PhyloP100		0.85
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
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs137852660; hg19: chr10-103534966;