rs3730204

Positions:

• chr12-102401736-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000618.5(IGF1):​c.*771T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 152,662 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: IGF1 NM_000618.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.972

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-102401736-A-G is Benign according to our data. Variant chr12-102401736-A-G is described in ClinVar as [Benign]. Clinvar id is 881950.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0108 (1640/152224) while in subpopulation SAS AF= 0.0193 (93/4824). AF 95% confidence interval is 0.0161. There are 18 homozygotes in gnomad4. There are 811 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1	NM_000618.5	c.*771T>C		3_prime_UTR_variant	4/4	ENST00000337514.11
LINC02456	XR_007063427.1	n.697-2377A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1	ENST00000337514.11	c.*771T>C		3_prime_UTR_variant	4/4	1	NM_000618.5	P1
HELLPAR	ENST00000626826.1	n.204152A>G		non_coding_transcript_exon_variant	1/1
LINC02456	ENST00000704346.1	n.1067-21335A>G		intron_variant, non_coding_transcript_variant
LINC02456	ENST00000635615.1	n.450-21335A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1642 AN: 152108 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0205 AC: 9 AN: 438 Hom.: 0 Cov.: 0 AF XY: 0.0226 AC XY: 6 AN XY: 266

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0108 AC: 1640 AN: 152224 Hom.: 18 Cov.: 32 AF XY: 0.0109 AC XY: 811 AN XY: 74436

Gnomad4 AFR AF: 0.00232

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0138 Hom.: 16

Bravo AF: 0.00862

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.9
DANN	Benign	0.69

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: rs3730204; hg19: chr12-102795514;