Genetic Variant IGF1:p.Val9Ala (chr12-102481791-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The XM_017019259.2(IGF1):c.26T>C(p.Val9Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 150,184 control chromosomes in the GnomAD database, including 42,941 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.75 ( 42935 hom., cov: 26)

Exomes 𝑓: 0.88 ( 6 hom. )

Consequence

IGF1
XM_017019259.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.155

Publications

215 publications found

Variant links:

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]

IGF1 links:

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

LINC02456 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644491.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1	NM_001414005.1		c.-108T>C		upstream_gene	N/A	NP_001400934.1
	IGF1	NM_001414007.1		c.-108T>C		upstream_gene	N/A	NP_001400936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1	ENST00000644491.1		c.-108T>C		upstream_gene	N/A	ENSP00000494228.1

Frequencies

GnomAD3 genomes

AF:

0.748

AC:

112212

AN:

150058

Hom.:

42935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.567

Gnomad AMI

AF:

0.798

Gnomad AMR

AF:

0.788

Gnomad ASJ

AF:

0.787

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.763

Gnomad FIN

AF:

0.800

Gnomad MID

AF:

0.820

Gnomad NFE

AF:

0.842

Gnomad OTH

AF:

0.772

GnomAD4 exome

AF:

0.875

AC:

AN:

Hom.:

Cov.:

AF XY:

0.833

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.833

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.748

AC:

112256

AN:

150168

Hom.:

42935

Cov.:

AF XY:

0.747

AC XY:

54696

AN XY:

73174

show subpopulations

African (AFR)

AF:

0.567

AC:

23142

AN:

40784

American (AMR)

AF:

0.788

AC:

11923

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.787

AC:

2728

AN:

3468

East Asian (EAS)

AF:

0.644

AC:

3248

AN:

5040

South Asian (SAS)

AF:

0.762

AC:

3610

AN:

4736

European-Finnish (FIN)

AF:

0.800

AC:

8073

AN:

10090

Middle Eastern (MID)

AF:

0.820

AC:

241

AN:

294

European-Non Finnish (NFE)

AF:

0.842

AC:

56964

AN:

67626

Other (OTH)

AF:

0.768

AC:

1601

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1249

2499

3748

4998

6247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.808

Hom.:

215141

Bravo

AF:

0.733

Asia WGS

AF:

0.687

AC:

2378

AN:

3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.7

(source)

DANN

Benign

0.71

PhyloP100

-0.15

PromoterAI

-0.0084

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over