rs1058696

chr15-98959298-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000875.5(IGF1R):c.*1856C>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 0.05 in 233,598 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (264 hom., cov: 33)
  • Exomes 𝑓: 0.045 (110 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

Genes affected

IGF1R (HGNC:5465): (insulin like growth factor 1 receptor) This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

SYNM-AS1 (HGNC:55421): (SYNM antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 15-98959298-C-T is Benign according to our data. Variant chr15-98959298-C-T is described in ClinVar as [Benign]. Clinvar id is 317517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.*1856C>T		3_prime_UTR_variant	21/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.*1856C>T		3_prime_UTR_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1	n.349-4910G>A		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.*1856C>T		3_prime_UTR_variant	21/21			A1

Frequencies

GnomAD3 genomes AF: 0.0524 AC: 7975 AN: 152222 Hom.: 263 Cov.: 33

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.0811

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.0644

Gnomad SAS AF: 0.0695

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0454 AC: 3693 AN: 81258 Hom.: 110 Cov.: 0 AF XY: 0.0445 AC XY: 1665 AN XY: 37422

Gnomad4 AFR exome AF: 0.0648

Gnomad4 AMR exome AF: 0.0880

Gnomad4 ASJ exome AF: 0.0256

Gnomad4 EAS exome AF: 0.0580

Gnomad4 SAS exome AF: 0.0571

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0409

Gnomad4 OTH exome AF: 0.0463

GnomAD4 genome AF: 0.0524 AC: 7981 AN: 152340 Hom.: 264 Cov.: 33 AF XY: 0.0526 AC XY: 3918 AN XY: 74502

Gnomad4 AFR AF: 0.0568

Gnomad4 AMR AF: 0.0813

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.0640

Gnomad4 SAS AF: 0.0696

Gnomad4 FIN AF: 0.0303

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0517 Hom.: 133

Bravo AF: 0.0558

Asia WGS AF: 0.0810 AC: 281 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 I resistance Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	12
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1058696; hg19: chr15-99502527;