rs7174918

Variant names:

• chr15-98708127-C-T
• rs7174918
• NM_000875.5:c.640+20C>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.640+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,598,980 control chromosomes in the GnomAD database, including 78,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5767 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72816 hom.)
• Consequence: IGF1R NM_000875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-98708127-C-T is Benign according to our data. Variant chr15-98708127-C-T is described in ClinVar as Benign. ClinVar VariationId is 1622379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.640+20C>T		intron	N/A	NP_000866.1
	IGF1R	NM_001291858.2		c.640+20C>T		intron	N/A	NP_001278787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.640+20C>T		intron	N/A	ENSP00000497069.1
	IGF1R	ENST00000559925.5	TSL:1	n.640+20C>T		intron	N/A
	IGF1R	ENST00000649865.1		c.640+20C>T		intron	N/A	ENSP00000496919.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39178 AN: 152032 Hom.: 5760 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.291 AC: 70650 AN: 242864 AF XY: 0.302

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.280

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.314 AC: 453804 AN: 1446830 Hom.: 72816 Cov.: 30 AF XY: 0.317 AC XY: 228567 AN XY: 720682

African (AFR) AF: 0.122 AC: 4052 AN: 33264

American (AMR) AF: 0.229 AC: 10223 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 9058 AN: 26040

East Asian (EAS) AF: 0.216 AC: 8564 AN: 39638

South Asian (SAS) AF: 0.361 AC: 31017 AN: 85860

European-Finnish (FIN) AF: 0.274 AC: 14311 AN: 52236

Middle Eastern (MID) AF: 0.379 AC: 1785 AN: 4712

European-Non Finnish (NFE) AF: 0.324 AC: 356152 AN: 1100542

Other (OTH) AF: 0.312 AC: 18642 AN: 59840

GnomAD4 genome AF: 0.258 AC: 39190 AN: 152150 Hom.: 5767 Cov.: 32 AF XY: 0.258 AC XY: 19208 AN XY: 74374

African (AFR) AF: 0.127 AC: 5263 AN: 41530

American (AMR) AF: 0.255 AC: 3900 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1195 AN: 3468

East Asian (EAS) AF: 0.223 AC: 1154 AN: 5172

South Asian (SAS) AF: 0.344 AC: 1663 AN: 4828

European-Finnish (FIN) AF: 0.261 AC: 2766 AN: 10584

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22240 AN: 67960

Other (OTH) AF: 0.281 AC: 593 AN: 2112

Alfa AF: 0.280 Hom.: 1784

Bravo AF: 0.248

Asia WGS AF: 0.305 AC: 1059 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.1
DANN	Benign	0.84
PhyloP100		-1.4
PromoterAI		0.047	Neutral
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: rs7174918; hg19: chr15-99251356; COSMIC: COSV51269321;