rs70961704

chr12-102402244-A-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.*263T>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 0.027 in 227,346 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (60 hom., cov: 32)
  • Exomes 𝑓: 0.026 (33 hom.)
• Consequence: IGF1 NM_000618.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.577

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=-0.88).
• BP6: Variant 12-102402244-A-T is Benign according to our data. Variant chr12-102402244-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 306905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102402244-A-T is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1	NM_000618.5	c.*263T>A		3_prime_UTR_variant	4/4	ENST00000337514.11
LINC02456	XR_007063427.1	n.697-1869A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1	ENST00000337514.11	c.*263T>A		3_prime_UTR_variant	4/4	1	NM_000618.5	P1
HELLPAR	ENST00000626826.1	n.204660A>T		non_coding_transcript_exon_variant	1/1
LINC02456	ENST00000704346.1	n.1067-20827A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4043 AN: 147580 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00120

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0587

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0270

GnomAD4 exome AF: 0.0262 AC: 2088 AN: 79674 Hom.: 33 Cov.: 0 AF XY: 0.0272 AC XY: 1199 AN XY: 44146

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.0284

Gnomad4 ASJ exome AF: 0.0495

Gnomad4 EAS exome AF: 0.0171

Gnomad4 SAS exome AF: 0.0485

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0232

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0274 AC: 4045 AN: 147672 Hom.: 60 Cov.: 32 AF XY: 0.0261 AC XY: 1882 AN XY: 72004

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.0253

Gnomad4 ASJ AF: 0.0804

Gnomad4 EAS AF: 0.0175

Gnomad4 SAS AF: 0.0587

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0300

Gnomad4 OTH AF: 0.0268

Alfa AF: 0.00380 Hom.: 0

Bravo AF: 0.0273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Growth delay due to insulin-like growth factor type 1 deficiency Benign:2

Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1KG: 3.5% (174/5008) total chromosomes, associated with insulin-like growth factor deficiency, sib does not carry variant -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.27
Dann	Benign	0.51

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: rs70961704; hg19: chr12-102796022;