12-102397002-A-T

Variant names:

• chr12-102397002-A-T
• rs1140655
• NM_000618.5:c.*5505T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000618.5(IGF1):​c.*5505T>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 0.669 in 394,082 control chromosomes in the GnomAD database, including 89,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32917 hom., cov: 29)
  • Exomes 𝑓: 0.68 (56335 hom.)
• Consequence: IGF1 NM_000618.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.836
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-102397002-A-T is Benign according to our data. Variant chr12-102397002-A-T is described in ClinVar as [Benign]. Clinvar id is 306840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1	NM_000618.5	c.*5505T>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.*5505T>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_000618.5	ENSP00000337612.7
HELLPAR	ENST00000626826.1	n.199418A>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
LINC02456	ENST00000635615.1	n.450-26069A>T		intron_variant	Intron 4 of 5	5
LINC02456	ENST00000704346.1	n.1067-26069A>T		intron_variant	Intron 9 of 10

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99278 AN: 151652 Hom.: 32912 Cov.: 29

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.635

GnomAD4 exome AF: 0.678 AC: 164310 AN: 242312 Hom.: 56335 Cov.: 0 AF XY: 0.678 AC XY: 83362 AN XY: 122872

African (AFR) AF: 0.554 AC: 3919 AN: 7074

American (AMR) AF: 0.660 AC: 4845 AN: 7338

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 5903 AN: 9094

East Asian (EAS) AF: 0.512 AC: 11602 AN: 22670

South Asian (SAS) AF: 0.705 AC: 1791 AN: 2542

European-Finnish (FIN) AF: 0.776 AC: 15821 AN: 20388

Middle Eastern (MID) AF: 0.621 AC: 786 AN: 1266

European-Non Finnish (NFE) AF: 0.700 AC: 109064 AN: 155834

Other (OTH) AF: 0.657 AC: 10579 AN: 16106

GnomAD4 genome AF: 0.654 AC: 99316 AN: 151770 Hom.: 32917 Cov.: 29 AF XY: 0.658 AC XY: 48762 AN XY: 74156

African (AFR) AF: 0.549 AC: 22710 AN: 41332

American (AMR) AF: 0.662 AC: 10105 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2251 AN: 3464

East Asian (EAS) AF: 0.538 AC: 2776 AN: 5156

South Asian (SAS) AF: 0.683 AC: 3282 AN: 4802

European-Finnish (FIN) AF: 0.788 AC: 8300 AN: 10532

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47681 AN: 67902

Other (OTH) AF: 0.630 AC: 1329 AN: 2110

Alfa AF: 0.680 Hom.: 4433

Bravo AF: 0.636

Asia WGS AF: 0.575 AC: 2001 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.81
DANN	Benign	0.80
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism (auto)

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: rs1140655; hg19: chr12-102790780;