11-69810396-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005247.4(FGF3):c.629G>A(p.Arg210Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,559,512 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (4 hom.)
• Consequence: FGF3 NM_005247.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.19

Genes affected

FGF3 (HGNC:3681): (fibroblast growth factor 3) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a chain Fibroblast growth factor 3 (size 221) in uniprot entity FGF3_HUMAN there are 18 pathogenic changes around while only 4 benign (82%) in NM_005247.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070419014).
• BP6: Variant 11-69810396-C-T is Benign according to our data. Variant chr11-69810396-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 731238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000394 (60/152318) while in subpopulation EAS AF= 0.0114 (59/5154). AF 95% confidence interval is 0.00911. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF3	NM_005247.4	c.629G>A	p.Arg210Gln	missense_variant	3/3	ENST00000334134.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF3	ENST00000334134.4	c.629G>A	p.Arg210Gln	missense_variant	3/3	1	NM_005247.4	P1
FGF3	ENST00000646078.1	n.476G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000704 AC: 134 AN: 190240 Hom.: 3 AF XY: 0.000666 AC XY: 69 AN XY: 103540

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00896

Gnomad SAS exome AF: 0.0000409

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000240

Gnomad OTH exome AF: 0.000212

GnomAD4 exome AF: 0.000205 AC: 288 AN: 1407194 Hom.: 4 Cov.: 30 AF XY: 0.000202 AC XY: 140 AN XY: 692884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00681

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000129

Gnomad4 OTH exome AF: 0.000259

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.000612

ExAC AF: 0.000669 AC: 80

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	13
Dann	Benign	0.95
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	0.80	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.29
Sift	Benign	0.30	T
Sift4G	Benign	0.21	T
Polyphen		0.024	B
Vest4		0.20
MVP		0.99
MPC		0.33
ClinPred		0.019	T
GERP RS		0.82
Varity_R		0.029
gMVP		0.47

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: rs115452181; hg19: chr11-69625164; COSMIC: COSV61925830;