15-98922244-C-T

Variant names:

• chr15-98922244-C-T
• rs3743262
• NM_000875.5:c.2298C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000875.5(IGF1R):​c.2298C>T​(p.Thr766Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0614 in 1,614,086 control chromosomes in the GnomAD database, including 5,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (660 hom., cov: 32)
  • Exomes 𝑓: 0.061 (5018 hom.)
• Consequence: IGF1R NM_000875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.664
• Publications: 34 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-98922244-C-T is Benign according to our data. Variant chr15-98922244-C-T is described in ClinVar as Benign. ClinVar VariationId is 193818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.664 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 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.2298C>T	p.Thr766Thr	synonymous	Exon 11 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.2298C>T	p.Thr766Thr	synonymous	Exon 11 of 21	NP_001278787.1	C9J5X1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	ENST00000650285.1	MANE Select	c.2298C>T	p.Thr766Thr	synonymous	Exon 11 of 21	ENSP00000497069.1	P08069
	IGF1R	ENST00000649865.1		c.2298C>T	p.Thr766Thr	synonymous	Exon 11 of 21	ENSP00000496919.1	C9J5X1
	IGF1R	ENST00000561049.1	TSL:5	n.489C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9288 AN: 152112 Hom.: 659 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0431

Gnomad OTH AF: 0.0570

GnomAD2 exomes AF: 0.0964 AC: 24228 AN: 251438 AF XY: 0.0935

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.0426

Gnomad OTH exome AF: 0.0653

GnomAD4 exome AF: 0.0614 AC: 89777 AN: 1461856 Hom.: 5018 Cov.: 33 AF XY: 0.0623 AC XY: 45288 AN XY: 727242

African (AFR) AF: 0.0121 AC: 406 AN: 33480

American (AMR) AF: 0.158 AC: 7046 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 526 AN: 26136

East Asian (EAS) AF: 0.330 AC: 13095 AN: 39700

South Asian (SAS) AF: 0.105 AC: 9062 AN: 86254

European-Finnish (FIN) AF: 0.126 AC: 6748 AN: 53418

Middle Eastern (MID) AF: 0.0213 AC: 123 AN: 5768

European-Non Finnish (NFE) AF: 0.0439 AC: 48844 AN: 1111982

Other (OTH) AF: 0.0650 AC: 3927 AN: 60396

GnomAD4 genome AF: 0.0610 AC: 9292 AN: 152230 Hom.: 660 Cov.: 32 AF XY: 0.0683 AC XY: 5083 AN XY: 74414

African (AFR) AF: 0.0150 AC: 622 AN: 41568

American (AMR) AF: 0.115 AC: 1763 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3470

East Asian (EAS) AF: 0.350 AC: 1805 AN: 5164

South Asian (SAS) AF: 0.131 AC: 631 AN: 4820

European-Finnish (FIN) AF: 0.128 AC: 1353 AN: 10582

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0430 AC: 2927 AN: 68012

Other (OTH) AF: 0.0574 AC: 121 AN: 2108

Alfa AF: 0.0454 Hom.: 530

Bravo AF: 0.0585

Asia WGS AF: 0.194 AC: 674 AN: 3478

EpiCase AF: 0.0399

EpiControl AF: 0.0388

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Growth delay due to insulin-like growth factor I resistance (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.0
DANN	Benign	0.41
PhyloP100		-0.66
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: rs3743262; hg19: chr15-99465473; COSMIC: COSV51269338; COSMIC: COSV51269338;