12-102397058-C-T

Variant names:

• chr12-102397058-C-T
• rs569070910
• NM_000618.5:c.*5449G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000618.5(IGF1):​c.*5449G>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 0.00108 in 366,040 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: IGF1 NM_000618.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.766
• Publications: 0 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]

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0017 (365/214200) while in subpopulation EAS AF = 0.0169 (347/20508). AF 95% confidence interval is 0.0155. There are 1 homozygotes in GnomAdExome4. There are 188 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1	NM_000618.5	c.*5449G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000337514.11	NP_000609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1	ENST00000337514.11	c.*5449G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_000618.5	ENSP00000337612.7
HELLPAR	ENST00000626826.1	n.199474C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
LINC02456	ENST00000635615.1	n.450-26013C>T		intron_variant	Intron 4 of 5	5
LINC02456	ENST00000704346.1	n.1067-26013C>T		intron_variant	Intron 9 of 10

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151722 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00445

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00170 AC: 365 AN: 214200 Hom.: 1 Cov.: 0 AF XY: 0.00173 AC XY: 188 AN XY: 108774

African (AFR) AF: 0.00 AC: 0 AN: 6346

American (AMR) AF: 0.00 AC: 0 AN: 6368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8170

East Asian (EAS) AF: 0.0169 AC: 347 AN: 20508

South Asian (SAS) AF: 0.00 AC: 0 AN: 1880

European-Finnish (FIN) AF: 0.0000582 AC: 1 AN: 17190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1116

European-Non Finnish (NFE) AF: 0.0000867 AC: 12 AN: 138416

Other (OTH) AF: 0.000352 AC: 5 AN: 14206

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151840 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74212

African (AFR) AF: 0.0000242 AC: 1 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00446 AC: 23 AN: 5158

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Growth delay due to insulin-like growth factor type 1 deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.26
PhyloP100		-0.77

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: rs569070910; hg19: chr12-102790836;