8-38426493-C-T

Variant names:

• chr8-38426493-C-T
• rs2293971
• NM_023110.3:c.622-248G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_023110.3(FGFR1):​c.622-248G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,192 control chromosomes in the GnomAD database, including 2,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (2993 hom., cov: 32)
• Consequence: FGFR1 NM_023110.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.311
• Publications: 9 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-38426493-C-T is Benign according to our data. Variant chr8-38426493-C-T is described in ClinVar as Benign. ClinVar VariationId is 1276722.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.622-248G>A		intron_variant	Intron 5 of 17	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.622-248G>A		intron_variant	Intron 5 of 17	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.616-248G>A		intron_variant	Intron 5 of 17	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.616-248G>A		intron_variant	Intron 6 of 18	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.616-248G>A		intron_variant	Intron 5 of 17	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.355-248G>A		intron_variant	Intron 4 of 16	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.349-248G>A		intron_variant	Intron 3 of 15	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.349-248G>A		intron_variant	Intron 4 of 16	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*313-248G>A		intron_variant	Intron 4 of 11	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27937 AN: 152074 Hom.: 2987 Cov.: 32

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.184 AC: 27964 AN: 152192 Hom.: 2993 Cov.: 32 AF XY: 0.180 AC XY: 13417 AN XY: 74404

African (AFR) AF: 0.0970 AC: 4028 AN: 41544

American (AMR) AF: 0.215 AC: 3288 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 521 AN: 3468

East Asian (EAS) AF: 0.307 AC: 1589 AN: 5170

South Asian (SAS) AF: 0.100 AC: 483 AN: 4826

European-Finnish (FIN) AF: 0.184 AC: 1945 AN: 10588

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.225 AC: 15309 AN: 67992

Other (OTH) AF: 0.193 AC: 407 AN: 2110

Alfa AF: 0.203 Hom.: 1147

Bravo AF: 0.190

Asia WGS AF: 0.192 AC: 666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.59
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs2293971; hg19: chr8-38284011; COSMIC: COSV58329254;