Genetic Variant IGF1:c.*2716G>A (chr12-102399791-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000618.5(IGF1):c.*2716G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 151,902 control chromosomes in the GnomAD database, including 15,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15586 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

IGF1
NM_000618.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.391

Publications

116 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:

HELLPAR (HGNC:43984): (HELLP associated long non-coding RNA)

HELLPAR 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 12-102399791-C-T is Benign according to our data. Variant chr12-102399791-C-T is described in ClinVar as Benign. ClinVar VariationId is 306880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGF1	NM_000618.5	MANE Select	c.*2716G>A	3_prime_UTR	Exon 4 of 4	NP_000609.1	Q5U743
IGF1	NM_001111283.3		c.*2750G>A	3_prime_UTR	Exon 5 of 5	NP_001104753.1	P05019-4
IGF1	NM_001414007.1		c.*2716G>A	3_prime_UTR	Exon 5 of 5	NP_001400936.1	Q5U743

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGF1	ENST00000337514.11	TSL:1 MANE Select	c.*2716G>A	3_prime_UTR	Exon 4 of 4	ENSP00000337612.7	P05019-2
HELLPAR	ENST00000626826.1	TSL:6	n.202207C>T	non_coding_transcript_exon	Exon 1 of 1
LINC02456	ENST00000635615.1	TSL:5	n.450-23280C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.446

AC:

67737

AN:

151784

Hom.:

15559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.541

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.487

Gnomad SAS

AF:

0.314

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.405

Gnomad OTH

AF:

0.450

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

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)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.446

AC:

67819

AN:

151902

Hom.:

15586

Cov.:

AF XY:

0.447

AC XY:

33170

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.542

AC:

22451

AN:

41444

American (AMR)

AF:

0.372

AC:

5668

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

1294

AN:

3462

East Asian (EAS)

AF:

0.487

AC:

2515

AN:

5164

South Asian (SAS)

AF:

0.313

AC:

1510

AN:

4822

European-Finnish (FIN)

AF:

0.515

AC:

5425

AN:

10544

Middle Eastern (MID)

AF:

0.404

AC:

118

AN:

292

European-Non Finnish (NFE)

AF:

0.405

AC:

27489

AN:

67904

Other (OTH)

AF:

0.451

AC:

952

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1879

3759

5638

7518

9397

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.414

Hom.:

40409

Bravo

AF:

0.446

Asia WGS

AF:

0.436

AC:

1511

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Growth delay due to insulin-like growth factor type 1 deficiency (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.97

(source)

DANN

Benign

0.30

PhyloP100

-0.39

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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