chr12-102396414-C-T

Position:

• chr12-102396414-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.*6093G>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 0.0905 in 153,244 control chromosomes in the GnomAD database, including 662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (655 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7 hom.)
• Consequence: IGF1 NM_000618.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0480

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=-0.82).
• BP6: Variant 12-102396414-C-T is Benign according to our data. Variant chr12-102396414-C-T is described in ClinVar as [Benign]. Clinvar id is 306836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1	NM_000618.5	c.*6093G>A		3_prime_UTR_variant	4/4	ENST00000337514.11	NP_000609.1
LINC02456	XR_007063427.1	n.697-7699C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1	ENST00000337514.11	c.*6093G>A		3_prime_UTR_variant	4/4	1	NM_000618.5	ENSP00000337612	P1
HELLPAR	ENST00000626826.1	n.198830C>T		non_coding_transcript_exon_variant	1/1
LINC02456	ENST00000704346.1	n.1067-26657C>T		intron_variant, non_coding_transcript_variant
LINC02456	ENST00000635615.1	n.450-26657C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0904 AC: 13748 AN: 152038 Hom.: 653 Cov.: 32

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0619

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0611

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0956

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.100 AC: 109 AN: 1088 Hom.: 7 Cov.: 0 AF XY: 0.101 AC XY: 54 AN XY: 534

Gnomad4 AFR exome AF: 0.0676

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0894

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.0904 AC: 13759 AN: 152156 Hom.: 655 Cov.: 32 AF XY: 0.0880 AC XY: 6547 AN XY: 74376

Gnomad4 AFR AF: 0.0848

Gnomad4 AMR AF: 0.0619

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.0611

Gnomad4 NFE AF: 0.0957

Gnomad4 OTH AF: 0.0941

Alfa AF: 0.0960 Hom.: 1014

Bravo AF: 0.0908

Asia WGS AF: 0.146 AC: 508 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	-0.82
CADD	Benign	9.2
DANN	Benign	0.72

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: rs6219; hg19: chr12-102790192;