rs3743249

Positions:

• chr15-98962194-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000875.5(IGF1R):​c.*4752G>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 0.327 in 233,090 control chromosomes in the GnomAD database, including 13,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9971 hom., cov: 33)
  • Exomes 𝑓: 0.30 (3831 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.820

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-98962194-G-T is Benign according to our data. Variant chr15-98962194-G-T is described in ClinVar as [Benign]. Clinvar id is 317589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.*4752G>T		3_prime_UTR_variant	21/21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.*4752G>T		3_prime_UTR_variant	21/21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.*4752G>T		3_prime_UTR_variant	21/21			ENSP00000496919.1
SYNM-AS1	ENST00000559468.1	n.348+3795C>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52126 AN: 151966 Hom.: 9949 Cov.: 33

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.323

GnomAD4 exome AF: 0.297 AC: 24027 AN: 81006 Hom.: 3831 Cov.: 0 AF XY: 0.294 AC XY: 10949 AN XY: 37242

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.295

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.343 AC: 52184 AN: 152084 Hom.: 9971 Cov.: 33 AF XY: 0.344 AC XY: 25601 AN XY: 74362

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.321

Alfa AF: 0.272 Hom.: 7912

Bravo AF: 0.361

Asia WGS AF: 0.378 AC: 1313 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 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. -

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	-0.83
CADD	Benign	3.7
DANN	Benign	0.61

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: rs3743249; hg19: chr15-99505423;