rs6214

Positions:

• chr12-102399791-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.391

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1	NM_000618.5	c.*2716G>A		3_prime_UTR_variant	4/4	ENST00000337514.11	NP_000609.1
LINC02456	XR_007063427.1	n.697-4322C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1	ENST00000337514.11	c.*2716G>A		3_prime_UTR_variant	4/4	1	NM_000618.5	ENSP00000337612	P1
HELLPAR	ENST00000626826.1	n.202207C>T		non_coding_transcript_exon_variant	1/1
LINC02456	ENST00000704346.1	n.1067-23280C>T		intron_variant, non_coding_transcript_variant
LINC02456	ENST00000635615.1	n.450-23280C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67737 AN: 151784 Hom.: 15559 Cov.: 32

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: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.446 AC: 67819 AN: 151902 Hom.: 15586 Cov.: 32 AF XY: 0.447 AC XY: 33170 AN XY: 74232

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.451

Alfa AF: 0.405 Hom.: 17490

Bravo AF: 0.446

Asia WGS AF: 0.436 AC: 1511 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.97
DANN	Benign	0.30

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

LitVar

Other links and lift over

dbSNP: rs6214; hg19: chr12-102793569;