chr8-38426158-C-T

Variant names:

• chr8-38426158-C-T
• rs121909635
• NM_023110.3:c.709G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_023110.3(FGFR1):​c.709G>A​(p.Gly237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G237D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.91
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• encephalocraniocutaneous lipomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hartsfield-Bixler-Demyer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
• hypogonadotropic hypogonadism 2 with or without anosmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteoglophonic dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Jackson-Weiss syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated trigonocephaly

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth agenesis

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255201 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-38426157-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2505415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to Hartsfield-Bixler-Demyer syndrome, Pfeiffer syndrome type 1, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism 2 with or without anosmia, osteoglophonic dysplasia, isolated trigonocephaly, septooptic dysplasia, Pfeiffer syndrome, tooth agenesis, hypogonadotropic hypogonadism, Kallmann syndrome, holoprosencephaly, Jackson-Weiss syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 8-38426158-C-T is Pathogenic according to our data. Variant chr8-38426158-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.709G>A	p.Gly237Ser	missense_variant	Exon 6 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.709G>A	p.Gly237Ser	missense_variant	Exon 6 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.703G>A	p.Gly235Ser	missense_variant	Exon 6 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.703G>A	p.Gly235Ser	missense_variant	Exon 7 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.703G>A	p.Gly235Ser	missense_variant	Exon 6 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.442G>A	p.Gly148Ser	missense_variant	Exon 5 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.436G>A	p.Gly146Ser	missense_variant	Exon 4 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.436G>A	p.Gly146Ser	missense_variant	Exon 5 of 17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*400G>A		non_coding_transcript_exon_variant	Exon 5 of 12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*400G>A		3_prime_UTR_variant	Exon 5 of 12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

May 04, 2023

Reproductive Endocrine Unit, Massachusetts General Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 18, 2006

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

FGFR1-related disorder Pathogenic:1

Jun 22, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FGFR1 c.709G>A (p.Gly237Ser) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250914 control chromosomes (gnomAD and publication data). c.709G>A has been reported in the literature in individuals affected with idiopathic hypogonadotropic hypogonadism as well as in two unaffected individuals (Pitteloud_2006, Shaw_2011, Wang_2014, Wang_2017, Men_2019). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant results in inhibiting proper folding of the FGFR1 and likely leading to the loss of cell-surface expression of FGFR1 (Pitteloud_2006). Additionally, another missense variant at the same codon, G237D, has been found in patients with Kallmann syndrome and segregated with the disease in one family (PMID: 16764984), indicating this residue is critical for FGFR1 protein function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;D;T;.;.;.;.;.;.;T;.;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;M;.;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D;D;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D;D;D;D;D;.;.
Polyphen		0.98	D;D;D;D;.;D;D;P;D;P;.;D;.;.
Vest4		0.97
MutPred		0.84		.;.;Gain of glycosylation at G237 (P = 0.0682);.;.;Gain of glycosylation at G237 (P = 0.0682);.;.;.;.;.;.;.;Gain of glycosylation at G237 (P = 0.0682);
MVP		0.93
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.82
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs121909635; hg19: chr8-38283676;