chr4-122889173-T-C

Position:

• chr4-122889173-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001361665.2(FGF2):​c.283-3038T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 152,154 control chromosomes in the GnomAD database, including 1,139 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 0.12 (1139 hom., cov: 32)
• Consequence: FGF2 NM_001361665.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400

Genes affected

FGF2 (HGNC:3676): (fibroblast growth factor 2) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members bind heparin and possess broad mitogenic and angiogenic activities. This protein has been implicated in diverse biological processes, such as limb and nervous system development, wound healing, and tumor growth. The mRNA for this gene contains multiple polyadenylation sites, and is alternatively translated from non-AUG (CUG) and AUG initiation codons, resulting in five different isoforms with distinct properties. The CUG-initiated isoforms are localized in the nucleus and are responsible for the intracrine effect, whereas, the AUG-initiated form is mostly cytosolic and is responsible for the paracrine and autocrine effects of this FGF. [provided by RefSeq, Jul 2008]

NUDT6 (HGNC:8053): (nudix hydrolase 6) This gene overlaps and lies on the opposite strand from FGF2 gene, and is thought to be the FGF2 antisense gene. The two genes are independently transcribed, and their expression shows an inverse relationship, suggesting that this antisense transcript may regulate FGF2 expression. This gene has also been shown to have hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF2 expression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.283-3038T>C		intron_variant		ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.682-3038T>C		intron_variant			NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000644866.2	c.283-3038T>C		intron_variant			NM_001361665.2	ENSP00000494222	P1
FGF2	ENST00000264498.9	c.682-3038T>C		intron_variant		1		ENSP00000264498
FGF2	ENST00000608478.1	c.283-3038T>C		intron_variant		1		ENSP00000477134	P1
NUDT6	ENST00000608639.1	n.173-217A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17826 AN: 152036 Hom.: 1138 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0846

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.125

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

GnomAD4 genome AF: 0.117 AC: 17838 AN: 152154 Hom.: 1139 Cov.: 32 AF XY: 0.113 AC XY: 8410 AN XY: 74398

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0829

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0845

Gnomad4 FIN AF: 0.0993

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.123

Alfa AF: 0.134 Hom.: 1405

Bravo AF: 0.116

Asia WGS AF: 0.0410 AC: 142 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.3
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs10452197; hg19: chr4-123810328;