15-98729846-C-T

Variant names:

• chr15-98729846-C-T
• rs7166287
• NM_000875.5:c.640+21739C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000875.5(IGF1R):​c.640+21739C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 152,042 control chromosomes in the GnomAD database, including 23,336 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23336 hom., cov: 32)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• Publications: 5 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]

IGF1R Gene-Disease associations (from GenCC):

• growth delay due to insulin-like growth factor I resistance

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.640+21739C>T		intron_variant	Intron 2 of 20	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.640+21739C>T		intron_variant	Intron 2 of 20		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000559925.5	n.640+21739C>T		intron_variant	Intron 2 of 9	1
IGF1R	ENST00000649865.1	c.640+21739C>T		intron_variant	Intron 2 of 20			ENSP00000496919.1
IGF1R	ENST00000558355.1	c.277+21739C>T		intron_variant	Intron 1 of 1	2		ENSP00000453630.1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81820 AN: 151924 Hom.: 23338 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.550

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.538 AC: 81819 AN: 152042 Hom.: 23336 Cov.: 32 AF XY: 0.538 AC XY: 39995 AN XY: 74336

African (AFR) AF: 0.342 AC: 14181 AN: 41480

American (AMR) AF: 0.537 AC: 8192 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2243 AN: 3470

East Asian (EAS) AF: 0.554 AC: 2860 AN: 5162

South Asian (SAS) AF: 0.524 AC: 2531 AN: 4826

European-Finnish (FIN) AF: 0.653 AC: 6889 AN: 10552

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.633 AC: 43025 AN: 67980

Other (OTH) AF: 0.545 AC: 1151 AN: 2112

Alfa AF: 0.574 Hom.: 3117

Bravo AF: 0.523

Asia WGS AF: 0.490 AC: 1706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.61
PhyloP100		0.17
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: rs7166287; hg19: chr15-99273075;