15-98649597-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.16G>A(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,600,800 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (8 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.49

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]

IRAIN (HGNC:):

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=0.008734435).
• BP6: Variant 15-98649597-G-A is Benign according to our data. Variant chr15-98649597-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1213041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000309 (46/148996) while in subpopulation SAS AF= 0.00505 (24/4756). AF 95% confidence interval is 0.00348. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.16G>A	p.Gly6Arg	missense_variant	1/21	ENST00000650285.1
IRAIN	NR_126453.2	n.1191C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.16G>A	p.Gly6Arg	missense_variant	1/21		NM_000875.5	P4
IGF1R	ENST00000559925.5	n.16G>A		non_coding_transcript_exon_variant	1/10	1
IGF1R	ENST00000649865.1	c.16G>A	p.Gly6Arg	missense_variant	1/21			A1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 46 AN: 148904 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00503

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000605 AC: 149 AN: 246136 Hom.: 3 AF XY: 0.000733 AC XY: 98 AN XY: 133756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000287

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.000334 AC: 485 AN: 1451804 Hom.: 8 Cov.: 31 AF XY: 0.000452 AC XY: 327 AN XY: 722712

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.000294

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00354

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000250

GnomAD4 genome AF: 0.000309 AC: 46 AN: 148996 Hom.: 1 Cov.: 32 AF XY: 0.000332 AC XY: 24 AN XY: 72364

Gnomad4 AFR AF: 0.0000246

Gnomad4 AMR AF: 0.000672

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00505

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000310

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000709 AC: 86

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22998174) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.52	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0087	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.34	N;.;N;.
MutationTaster	Benign	0.84	D;D
PrimateAI	Uncertain	0.76	T
Polyphen		0.93	P;P;P;P
Vest4		0.40, 0.38
MutPred		0.31		Gain of MoRF binding (P = 0.0046);Gain of MoRF binding (P = 0.0046);Gain of MoRF binding (P = 0.0046);Gain of MoRF binding (P = 0.0046);
MVP		0.98
MPC		1.2
ClinPred		0.033	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.15
gMVP		0.52

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: rs199652097; hg19: chr15-99192826;