rs2654981

Variant names:

• chr15-98961900-C-G
• rs2654981
• NM_000875.5:c.*4458C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-98961900-C-G
• chr15-98961900-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000875.5(IGF1R):​c.*4458C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 233,094 control chromosomes in the GnomAD database, including 24,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15498 hom., cov: 33)
  • Exomes 𝑓: 0.47 (9073 hom.)
• Consequence: IGF1R NM_000875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.573
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-98961900-C-G is Benign according to our data. Variant chr15-98961900-C-G is described in CliVar as Benign. Clinvar id is 317580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.*4458C>G		3_prime_UTR_variant	Exon 21 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.*4458C>G		3_prime_UTR_variant	Exon 21 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.*4458C>G		3_prime_UTR_variant	Exon 21 of 21			ENSP00000496919.1
SYNM-AS1	ENST00000559468.1	n.348+4089G>C		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67804 AN: 152004 Hom.: 15486 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.433

GnomAD4 exome AF: 0.470 AC: 38088 AN: 80972 Hom.: 9073 Cov.: 0 AF XY: 0.470 AC XY: 17487 AN XY: 37208

African (AFR) AF: 0.342 AC: 1333 AN: 3896

American (AMR) AF: 0.501 AC: 1252 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 2218 AN: 5124

East Asian (EAS) AF: 0.526 AC: 6000 AN: 11402

South Asian (SAS) AF: 0.401 AC: 281 AN: 700

European-Finnish (FIN) AF: 0.391 AC: 25 AN: 64

Middle Eastern (MID) AF: 0.392 AC: 193 AN: 492

European-Non Finnish (NFE) AF: 0.475 AC: 23739 AN: 50020

Other (OTH) AF: 0.450 AC: 3047 AN: 6774

GnomAD4 genome AF: 0.446 AC: 67841 AN: 152122 Hom.: 15498 Cov.: 33 AF XY: 0.446 AC XY: 33177 AN XY: 74378

African (AFR) AF: 0.346 AC: 14370 AN: 41480

American (AMR) AF: 0.492 AC: 7518 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1501 AN: 3470

East Asian (EAS) AF: 0.553 AC: 2867 AN: 5180

South Asian (SAS) AF: 0.402 AC: 1943 AN: 4832

European-Finnish (FIN) AF: 0.467 AC: 4939 AN: 10574

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 33056 AN: 67988

Other (OTH) AF: 0.430 AC: 909 AN: 2112

Alfa AF: 0.346 Hom.: 1074

Bravo AF: 0.446

Asia WGS AF: 0.479 AC: 1668 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

Jan 12, 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	-0.84
CADD	Benign	5.6
DANN	Benign	0.64
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2654981; hg19: chr15-99505129;