19-48756272-A-G

Variant names:

• chr19-48756272-A-G
• rs838133
• NM_019113.4:c.36A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_019113.4(FGF21):​c.36A>G​(p.Gly12Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 1,613,498 control chromosomes in the GnomAD database, including 298,436 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. Synonymous variant affecting the same amino acid position (i.e. G12G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.64 (32197 hom., cov: 31)
  • Exomes 𝑓: 0.59 (266239 hom.)
• Consequence: FGF21 NM_019113.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.114
• Publications: 137 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP7: Synonymous conserved (PhyloP=-0.114 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019113.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF21	NM_019113.4	MANE Select	c.36A>G	p.Gly12Gly	synonymous	Exon 2 of 4	NP_061986.1	Q9NSA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF21	ENST00000593756.6	TSL:1 MANE Select	c.36A>G	p.Gly12Gly	synonymous	Exon 2 of 4	ENSP00000471477.1	Q9NSA1
	FGF21	ENST00000222157.5	TSL:1	c.36A>G	p.Gly12Gly	synonymous	Exon 1 of 3	ENSP00000222157.3	Q9NSA1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97574 AN: 151876 Hom.: 32158 Cov.: 31

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.777

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.627

GnomAD2 exomes AF: 0.666 AC: 166889 AN: 250524 AF XY: 0.660

Gnomad AFR exome AF: 0.706

Gnomad AMR exome AF: 0.784

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.995

Gnomad FIN exome AF: 0.620

Gnomad NFE exome AF: 0.566

Gnomad OTH exome AF: 0.626

GnomAD4 exome AF: 0.595 AC: 869298 AN: 1461502 Hom.: 266239 Cov.: 61 AF XY: 0.599 AC XY: 435703 AN XY: 727054

African (AFR) AF: 0.707 AC: 23669 AN: 33468

American (AMR) AF: 0.775 AC: 34631 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 14406 AN: 26130

East Asian (EAS) AF: 0.993 AC: 39400 AN: 39680

South Asian (SAS) AF: 0.755 AC: 65073 AN: 86238

European-Finnish (FIN) AF: 0.620 AC: 33075 AN: 53314

Middle Eastern (MID) AF: 0.540 AC: 3111 AN: 5762

European-Non Finnish (NFE) AF: 0.557 AC: 619618 AN: 1111834

Other (OTH) AF: 0.601 AC: 36315 AN: 60378

GnomAD4 genome AF: 0.643 AC: 97669 AN: 151996 Hom.: 32197 Cov.: 31 AF XY: 0.651 AC XY: 48350 AN XY: 74278

African (AFR) AF: 0.700 AC: 29033 AN: 41460

American (AMR) AF: 0.689 AC: 10505 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1908 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5138 AN: 5168

South Asian (SAS) AF: 0.777 AC: 3739 AN: 4812

European-Finnish (FIN) AF: 0.625 AC: 6586 AN: 10544

Middle Eastern (MID) AF: 0.524 AC: 152 AN: 290

European-Non Finnish (NFE) AF: 0.569 AC: 38657 AN: 67972

Other (OTH) AF: 0.633 AC: 1339 AN: 2116

Alfa AF: 0.595 Hom.: 69002

Bravo AF: 0.648

Asia WGS AF: 0.890 AC: 3093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.2
DANN	Benign	0.60
PhyloP100		-0.11
PromoterAI		-0.0013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs838133; hg19: chr19-49259529; COSMIC: COSV55810289; COSMIC: COSV55810289;