19-48756967-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019113.4(FGF21):c.277A>G(p.Ile93Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGF21 NM_019113.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

Genes affected

FGF21 (HGNC:3678): (fibroblast growth factor 21) Theis gene encodes 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. This protein is a secreted endocrine factor that functions as a major metabolic regulator. The encoded protein stimulates the uptake of glucose in adipose tissue. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32767966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF21	NM_019113.4	c.277A>G	p.Ile93Val	missense_variant	3/4	ENST00000593756.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF21	ENST00000593756.6	c.277A>G	p.Ile93Val	missense_variant	3/4	1	NM_019113.4	P1
FGF21	ENST00000222157.5	c.277A>G	p.Ile93Val	missense_variant	2/3	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.277A>G (p.I93V) alteration is located in exon 2 (coding exon 2) of the FGF21 gene. This alteration results from a A to G substitution at nucleotide position 277, causing the isoleucine (I) at amino acid position 93 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.69	N
PrimateAI	Uncertain	0.57	T
Sift4G	Benign	0.20	T;T
Polyphen		0.014	B;B
Vest4		0.38
MutPred		0.65		Gain of MoRF binding (P = 0.1749);Gain of MoRF binding (P = 0.1749);
MVP		0.94
MPC		0.035
ClinPred		0.30	T
GERP RS		3.1
Varity_R		0.084
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49260224;