chr12-102396123-G-A

Variant names:

• chr12-102396123-G-A
• rs6222
• NM_000618.5:c.*6384C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000618.5(IGF1):​c.*6384C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 152,238 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (55 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: 2.37

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-102396123-G-A is Benign according to our data. Variant chr12-102396123-G-A is described in ClinVar as [Benign]. Clinvar id is 306831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.025 (3807/152238) while in subpopulation AFR AF= 0.0335 (1391/41546). AF 95% confidence interval is 0.032. There are 55 homozygotes in gnomad4. There are 1849 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1	NM_000618.5	c.*6384C>T		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	c.*6384C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_000618.5	ENSP00000337612.7
HELLPAR	ENST00000626826.1	n.198539G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
LINC02456	ENST00000635615.1	n.450-26948G>A		intron_variant	Intron 4 of 5	5
LINC02456	ENST00000704346.1	n.1067-26948G>A		intron_variant	Intron 9 of 10

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3810 AN: 152120 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0197

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: 0.0250 AC: 3807 AN: 152238 Hom.: 55 Cov.: 32 AF XY: 0.0248 AC XY: 1849 AN XY: 74430

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0216 Hom.: 39

Bravo AF: 0.0245

Asia WGS AF: 0.00289 AC: 10 AN: 3476

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 13, 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	-0.45
CADD	Benign	12
DANN	Benign	0.74

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: rs6222; hg19: chr12-102789901;