rs727505371

Positions:

chr8-38421839-TAG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP3PP5

The NM_023110.3(FGFR1):c.1037_1038del(p.Ser346TyrfsTer61) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

FGFR1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 8-38421839-TAG-T is Pathogenic according to our data. Variant chr8-38421839-TAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180154.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}. Variant chr8-38421839-TAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR1	NM_023110.3 linkuse as main transcript	c.1037_1038del	p.Ser346TyrfsTer61	frameshift_variant	8/18	ENST00000447712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR1	ENST00000447712.7 linkuse as main transcript	c.1037_1038del	p.Ser346TyrfsTer61	frameshift_variant	8/18	1	NM_023110.3	P4	P11362-1
	ENST00000528407.1 linkuse as main transcript			upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249924

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

Delayed puberty

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 07, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 180154). This premature translational stop signal has been observed in individual(s) with Kallman syndrome (PMID: 23533228). This variant is present in population databases (rs727505371, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser346Tyrfs*61) in the FGFR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FGFR1 are known to be pathogenic (PMID: 12627230). -

Hypogonadotropic hypogonadism 2 with or without anosmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Reproductive Endocrine Unit, Massachusetts General Hospital

May 04, 2023

The variant NM_023110.2:c.1037_1038del, p.(Ser346Tyrfs*61) het has been classified as VUS based on the variant meeting the following ACMG Criteria: PVS1,PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.60

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.60

Position offset: 9

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