chr15-98924705-A-C

Variant names:

• chr15-98924705-A-C
• rs1464430
• NM_000875.5:c.2782+21A>C

Variant summary

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

The NM_000875.5(IGF1R):​c.2782+21A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,604,826 control chromosomes in the GnomAD database, including 90,307 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 0.41 (13956 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76351 hom.)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.47
• Publications: 23 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 = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.2782+21A>C		intron_variant	Intron 13 of 20	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.2782+21A>C		intron_variant	Intron 13 of 20		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000560972.1	n.85+21A>C		intron_variant	Intron 1 of 3	1
IGF1R	ENST00000649865.1	c.2782+21A>C		intron_variant	Intron 13 of 20			ENSP00000496919.1
IGF1R	ENST00000560343.1	n.*69A>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.410 AC: 60959 AN: 148624 Hom.: 13937 Cov.: 32

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.394

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.393

GnomAD2 exomes AF: 0.344 AC: 84174 AN: 244764 AF XY: 0.333

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.290

Gnomad FIN exome AF: 0.273

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.317 AC: 461961 AN: 1456096 Hom.: 76351 Cov.: 31 AF XY: 0.315 AC XY: 227930 AN XY: 724720

African (AFR) AF: 0.646 AC: 21519 AN: 33298

American (AMR) AF: 0.413 AC: 18459 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 9176 AN: 26108

East Asian (EAS) AF: 0.242 AC: 9612 AN: 39676

South Asian (SAS) AF: 0.270 AC: 23253 AN: 86120

European-Finnish (FIN) AF: 0.273 AC: 14601 AN: 53406

Middle Eastern (MID) AF: 0.349 AC: 1981 AN: 5674

European-Non Finnish (NFE) AF: 0.310 AC: 343169 AN: 1106980

Other (OTH) AF: 0.336 AC: 20191 AN: 60156

GnomAD4 genome AF: 0.410 AC: 61014 AN: 148730 Hom.: 13956 Cov.: 32 AF XY: 0.407 AC XY: 29509 AN XY: 72586

African (AFR) AF: 0.654 AC: 26120 AN: 39966

American (AMR) AF: 0.422 AC: 6292 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1233 AN: 3392

East Asian (EAS) AF: 0.286 AC: 1398 AN: 4888

South Asian (SAS) AF: 0.289 AC: 1273 AN: 4406

European-Finnish (FIN) AF: 0.272 AC: 2850 AN: 10480

Middle Eastern (MID) AF: 0.389 AC: 109 AN: 280

European-Non Finnish (NFE) AF: 0.307 AC: 20721 AN: 67424

Other (OTH) AF: 0.388 AC: 801 AN: 2062

Alfa AF: 0.329 Hom.: 3474

Bravo AF: 0.426

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.024
DANN	Benign	0.70
PhyloP100		-2.5
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: rs1464430; hg19: chr15-99467934; COSMIC: COSV51296987; COSMIC: COSV51296987;