12-102480377-C-T

Variant names:

• chr12-102480377-C-T
• rs3730195
• NM_000618.5:c.5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000618.5(IGF1):​c.5G>A​(p.Gly2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1 NM_000618.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 18 publications found

Genes affected

IGF1 (HGNC:5464): (insulin like growth factor 1) The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Sep 2015]

LINC02456 (HGNC:53389): (long intergenic non-protein coding RNA 2456)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2744226).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000618.5. 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
	IGF1	NM_000618.5	MANE Select	c.5G>A	p.Gly2Glu	missense	Exon 1 of 4	NP_000609.1	Q5U743
	IGF1	NM_001111285.3		c.5G>A	p.Gly2Glu	missense	Exon 1 of 4	NP_001104755.1	P05019-1
	IGF1	NM_001414005.1		c.5G>A	p.Gly2Glu	missense	Exon 2 of 5	NP_001400934.1	P05019-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1	ENST00000337514.11	TSL:1 MANE Select	c.5G>A	p.Gly2Glu	missense	Exon 1 of 4	ENSP00000337612.7	P05019-2
	IGF1	ENST00000307046.8	TSL:1	c.5G>A	p.Gly2Glu	missense	Exon 1 of 4	ENSP00000302665.8	P05019-1
	IGF1	ENST00000392904.5	TSL:5	c.5G>A	p.Gly2Glu	missense	Exon 2 of 6	ENSP00000376637.1	P05019-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.28
Eigen_PC	Benign	0.00085
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.48	N
PhyloP100		3.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.33
Sift	Benign	0.61	T
Sift4G	Benign	0.58	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.26		Gain of ubiquitination at K3 (P = 0.0415)
MVP		0.93
MPC		1.0
ClinPred		0.72	D
GERP RS		5.2
PromoterAI		0.030	Neutral
Varity_R		0.064
gMVP		0.50
Mutation Taster		=83/17	polymorphism

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: rs3730195; hg19: chr12-102874155;