chr15-98942702-T-A

Variant names:

• chr15-98942702-T-A
• rs41497346
• NM_000875.5:c.3458-221T>A

Variant summary

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

The NM_000875.5(IGF1R):​c.3458-221T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,132 control chromosomes in the GnomAD database, including 4,596 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 0.22 (4596 hom., cov: 33)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.161
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.3458-221T>A		intron_variant	Intron 18 of 20	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.3458-221T>A		intron_variant	Intron 18 of 20		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000649865.1	c.3455-221T>A		intron_variant	Intron 18 of 20			ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33446 AN: 152014 Hom.: 4594 Cov.: 33

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.220 AC: 33458 AN: 152132 Hom.: 4596 Cov.: 33 AF XY: 0.222 AC XY: 16544 AN XY: 74380

African (AFR) AF: 0.385 AC: 15943 AN: 41462

American (AMR) AF: 0.222 AC: 3392 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3472

East Asian (EAS) AF: 0.317 AC: 1640 AN: 5172

South Asian (SAS) AF: 0.202 AC: 974 AN: 4820

European-Finnish (FIN) AF: 0.146 AC: 1543 AN: 10592

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8663 AN: 67990

Other (OTH) AF: 0.209 AC: 443 AN: 2116

Alfa AF: 0.175 Hom.: 361

Bravo AF: 0.233

Asia WGS AF: 0.248 AC: 862 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.68
DANN	Benign	0.44
PhyloP100		-0.16
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: rs41497346; hg19: chr15-99485931;