rs61740877

chr15-98911326-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000875.5(IGF1R):c.1474G>A(p.Val492Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,614,068 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, IGF1R
• BP4: Computational evidence support a benign effect (MetaRNN=0.0044712424).
• BP6: Variant 15-98911326-G-A is Benign according to our data. Variant chr15-98911326-G-A is described in ClinVar as [Benign]. Clinvar id is 198439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-98911326-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00219 (334/152204) while in subpopulation AFR AF= 0.00758 (315/41530). AF 95% confidence interval is 0.0069. There are 5 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.1474G>A	p.Val492Ile	missense_variant	7/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.1474G>A	p.Val492Ile	missense_variant	7/21		NM_000875.5	P4

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152086 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000569 AC: 143 AN: 251440 Hom.: 0 AF XY: 0.000390 AC XY: 53 AN XY: 135894

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1461864 Hom.: 2 Cov.: 32 AF XY: 0.000193 AC XY: 140 AN XY: 727238

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152204 Hom.: 5 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74414

Gnomad4 AFR AF: 0.00758

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000452 Hom.: 1

Bravo AF: 0.00252

ESP6500AA AF: 0.00819 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 30, 2014

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.42	T;.;T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0045	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.49	N;.;N;.;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.48	T
Polyphen		0.0	B;B;B;B;.
Vest4		0.12, 0.13
MVP		0.52
MPC		0.50
ClinPred		0.0041	T
GERP RS		2.7
Varity_R		0.036
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs61740877; hg19: chr15-99454555; COSMIC: COSV51272375; COSMIC: COSV51272375;