rs6996321

Variant names:

• chr8-38464828-A-G
• rs6996321
• NM_023110.3:c.-89+3153T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023110.3(FGFR1):​c.-89+3153T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 152,094 control chromosomes in the GnomAD database, including 29,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29723 hom., cov: 32)
• Consequence: FGFR1 NM_023110.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255
• Publications: 25 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.-89+3153T>C		intron_variant	Intron 1 of 17	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.-89+3153T>C		intron_variant	Intron 1 of 17	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.-89+3153T>C		intron_variant	Intron 1 of 17	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.-249+2844T>C		intron_variant	Intron 1 of 18	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.-89+2844T>C		intron_variant	Intron 1 of 17	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.-89+3153T>C		intron_variant	Intron 1 of 16	1		ENSP00000348537.5
FGFR1	ENST00000326324.10	c.-89+3153T>C		intron_variant	Intron 1 of 16	1		ENSP00000327229.6

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94556 AN: 151978 Hom.: 29711 Cov.: 32

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.580

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

GnomAD4 genome AF: 0.622 AC: 94601 AN: 152094 Hom.: 29723 Cov.: 32 AF XY: 0.625 AC XY: 46437 AN XY: 74342

African (AFR) AF: 0.627 AC: 26031 AN: 41486

American (AMR) AF: 0.632 AC: 9662 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 2161 AN: 3468

East Asian (EAS) AF: 0.605 AC: 3132 AN: 5180

South Asian (SAS) AF: 0.822 AC: 3963 AN: 4820

European-Finnish (FIN) AF: 0.583 AC: 6160 AN: 10562

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41633 AN: 67978

Other (OTH) AF: 0.585 AC: 1235 AN: 2112

Alfa AF: 0.619 Hom.: 119326

Bravo AF: 0.619

Asia WGS AF: 0.727 AC: 2527 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.6
DANN	Benign	0.59
PhyloP100		-0.26
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: rs6996321; hg19: chr8-38322346;