chr8-38428048-A-G

Variant names:

• chr8-38428048-A-G
• rs397515481
• NM_023110.3:c.494T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_023110.3(FGFR1):​c.494T>C​(p.Leu165Ser) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.32
• Publications: 10 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.873
• PP5: Variant 8-38428048-A-G is Pathogenic according to our data. Variant chr8-38428048-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 66079.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.494T>C	p.Leu165Ser	missense_variant	Exon 5 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.494T>C	p.Leu165Ser	missense_variant	Exon 5 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.488T>C	p.Leu163Ser	missense_variant	Exon 5 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.488T>C	p.Leu163Ser	missense_variant	Exon 6 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.488T>C	p.Leu163Ser	missense_variant	Exon 5 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.227T>C	p.Leu76Ser	missense_variant	Exon 4 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.221T>C	p.Leu74Ser	missense_variant	Exon 3 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.221T>C	p.Leu74Ser	missense_variant	Exon 4 of 17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*185T>C		non_coding_transcript_exon_variant	Exon 4 of 12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*185T>C		3_prime_UTR_variant	Exon 4 of 12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hartsfield-Bixler-Demyer syndrome Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;D;T;.;.;.;.;.;.;T;.;T;T;.;T;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.7	.;.;L;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.7	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;.;.;.;D;.
Polyphen		0.99	D;D;D;D;.;D;D;D;D;D;.;D;.;.;.;.;.
Vest4		0.89
MutPred		0.52		.;.;Loss of stability (P = 0.0275);.;.;Loss of stability (P = 0.0275);.;.;.;.;.;.;.;Loss of stability (P = 0.0275);.;.;.;
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397515481; hg19: chr8-38285566;