3-192170334-C-G

Variant names:

• chr3-192170334-C-G
• rs2046917
• NM_004113.6:c.427+124G>C

Variant summary

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

The NM_004113.6(FGF12):​c.427+124G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 688,786 control chromosomes in the GnomAD database, including 81,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (26048 hom., cov: 27)
  • Exomes 𝑓: 0.44 (55757 hom.)
• Consequence: FGF12 NM_004113.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05
• Publications: 3 publications found

Genes affected

FGF12 (HGNC:3668): (fibroblast growth factor 12) 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 growth factor lacks the N-terminal signal sequence present in most of the FGF family members, but it contains clusters of basic residues that have been demonstrated to act as a nuclear localization signal. When transfected into mammalian cells, this protein accumulated in the nucleus, but was not secreted. The specific function of this gene has not yet been determined. [provided by RefSeq, Dec 2019]

FGF12 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 47

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD 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=-0.85).
• BP6: Variant 3-192170334-C-G is Benign according to our data. Variant chr3-192170334-C-G is described in ClinVar as Benign. ClinVar VariationId is 1234571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF12	NM_004113.6	c.427+124G>C		intron_variant	Intron 5 of 5	ENST00000445105.7	NP_004104.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF12	ENST00000445105.7	c.427+124G>C		intron_variant	Intron 5 of 5	1	NM_004113.6	ENSP00000393686.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 81942 AN: 149534 Hom.: 25977 Cov.: 27

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.514

GnomAD4 exome AF: 0.442 AC: 238510 AN: 539150 Hom.: 55757 AF XY: 0.449 AC XY: 127849 AN XY: 284996

African (AFR) AF: 0.885 AC: 12441 AN: 14058

American (AMR) AF: 0.525 AC: 11118 AN: 21178

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 6313 AN: 14040

East Asian (EAS) AF: 0.543 AC: 17720 AN: 32614

South Asian (SAS) AF: 0.609 AC: 30224 AN: 49662

European-Finnish (FIN) AF: 0.402 AC: 18308 AN: 45566

Middle Eastern (MID) AF: 0.477 AC: 974 AN: 2042

European-Non Finnish (NFE) AF: 0.386 AC: 127968 AN: 331516

Other (OTH) AF: 0.472 AC: 13444 AN: 28474

GnomAD4 genome AF: 0.548 AC: 82061 AN: 149636 Hom.: 26048 Cov.: 27 AF XY: 0.550 AC XY: 40103 AN XY: 72880

African (AFR) AF: 0.883 AC: 35948 AN: 40722

American (AMR) AF: 0.501 AC: 7505 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1485 AN: 3458

East Asian (EAS) AF: 0.605 AC: 3051 AN: 5040

South Asian (SAS) AF: 0.620 AC: 2932 AN: 4732

European-Finnish (FIN) AF: 0.398 AC: 3907 AN: 9818

Middle Eastern (MID) AF: 0.455 AC: 130 AN: 286

European-Non Finnish (NFE) AF: 0.381 AC: 25730 AN: 67618

Other (OTH) AF: 0.518 AC: 1076 AN: 2076

Alfa AF: 0.448 Hom.: 2127

Bravo AF: 0.571

Asia WGS AF: 0.671 AC: 2333 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 06, 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	-0.85
CADD	Benign	1.1
DANN	Benign	0.74
PhyloP100		-1.0
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: rs2046917; hg19: chr3-191888123; COSMIC: COSV53194703; COSMIC: COSV53194703;