Genetic Variant IGF1:c.*5332G>A (chr12-102397175-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000618.5(IGF1):c.*5332G>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 0.0000293 in 238,840 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: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

IGF1
NM_000618.5 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.238

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

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.*5332G>A	3_prime_UTR	Exon 4 of 4	NP_000609.1	Q5U743
IGF1	NM_001111283.3		c.*5366G>A	3_prime_UTR	Exon 5 of 5	NP_001104753.1	P05019-4
IGF1	NM_001414007.1		c.*5332G>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.*5332G>A	3_prime_UTR	Exon 4 of 4	ENSP00000337612.7	P05019-2
HELLPAR	ENST00000626826.1	TSL:6	n.199591C>T	non_coding_transcript_exon	Exon 1 of 1
LINC02456	ENST00000635615.1	TSL:5	n.450-25896C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151528

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000836

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

87312

Hom.:

Cov.:

AF XY:

0.0000450

AC XY:

AN XY:

44410

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

3102

American (AMR)

AF:

0.00

AC:

AN:

2670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3624

East Asian (EAS)

AF:

0.00

AC:

AN:

7532

South Asian (SAS)

AF:

0.00256

AC:

AN:

782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

486

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57896

Other (OTH)

AF:

0.00

AC:

AN:

6116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151528

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41198

American (AMR)

AF:

0.00

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000836

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.56

(source)

DANN

Benign

0.31

PhyloP100

-0.24

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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