rs56341011

Variant names:

• chr8-38413948-C-T
• rs56341011
• NM_023110.3:c.2262G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-38413948-C-T
• chr8-38413948-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_023110.3(FGFR1):​c.2262G>A​(p.Leu754Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,614,082 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (95 hom.)
• Consequence: FGFR1 NM_023110.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.243
• Publications: 8 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: G2P, Ambry Genetics, Orphanet, ClinGen
• hypogonadotropic hypogonadism 2 with or without anosmia

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

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

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-38413948-C-T is Benign according to our data. Variant chr8-38413948-C-T is described in ClinVar as Benign. ClinVar VariationId is 362893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.243 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00705 (1073/152262) while in subpopulation AMR AF = 0.0141 (215/15300). AF 95% confidence interval is 0.0125. There are 6 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023110.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	NM_023110.3	MANE Select	c.2262G>A	p.Leu754Leu	synonymous	Exon 17 of 18	NP_075598.2	P11362-1
	FGFR1	NM_001174067.2		c.2355G>A	p.Leu785Leu	synonymous	Exon 18 of 19	NP_001167538.1	P11362-21
	FGFR1	NM_001354367.2		c.2256G>A	p.Leu752Leu	synonymous	Exon 17 of 18	NP_001341296.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR1	ENST00000447712.7	TSL:1 MANE Select	c.2262G>A	p.Leu754Leu	synonymous	Exon 17 of 18	ENSP00000400162.2	P11362-1
	FGFR1	ENST00000425967.8	TSL:1	c.2250G>A	p.Leu750Leu	synonymous	Exon 17 of 18	ENSP00000393312.4	A0A8I3B1S4
	FGFR1	ENST00000397091.9	TSL:1	c.2256G>A	p.Leu752Leu	synonymous	Exon 17 of 18	ENSP00000380280.5	P11362-7

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1073 AN: 152144 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00668 AC: 1670 AN: 250176 AF XY: 0.00655

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000977

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00951

GnomAD4 exome AF: 0.00983 AC: 14367 AN: 1461820 Hom.: 95 Cov.: 32 AF XY: 0.00946 AC XY: 6877 AN XY: 727210

African (AFR) AF: 0.00179 AC: 60 AN: 33480

American (AMR) AF: 0.0112 AC: 500 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 166 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53410

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 13002 AN: 1111978

Other (OTH) AF: 0.00901 AC: 544 AN: 60390

GnomAD4 genome AF: 0.00705 AC: 1073 AN: 152262 Hom.: 6 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74442

African (AFR) AF: 0.00265 AC: 110 AN: 41564

American (AMR) AF: 0.0141 AC: 215 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 684 AN: 68006

Other (OTH) AF: 0.0128 AC: 27 AN: 2108

Alfa AF: 0.00870 Hom.: 3

Bravo AF: 0.00859

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0128

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Craniosynostosis syndrome (1)
-	-	1	Hypogonadotropic hypogonadism 2 with or without anosmia (1)
-	-	1	Osteoglophonic dysplasia (1)
-	-	1	Pfeiffer syndrome;C0406612:Encephalocraniocutaneous lipomatosis;C0432122:Trigonocephaly 1;C0432283:Osteoglophonic dysplasia;C0795998:Jackson-Weiss syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia;C1845146:Hartsfield-Bixler-Demyer syndrome (1)
-	-	1	Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia (1)
-	-	1	Trigonocephaly 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs56341011; hg19: chr8-38271466; COSMIC: COSV58336989;