15-98649652-C-G

Variant names:

• chr15-98649652-C-G
• rs1013771934
• NM_000875.5:c.71C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000875.5(IGF1R):​c.71C>G​(p.Ser24Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,458,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.440

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:50365): (IGF1R antisense imprinted non-protein coding RNA) This gene expresses a long non-coding RNA in antisense to the insulin-like growth factor type I receptor (IGF1R) gene. This transcript is imprinted and expressed from the paternal allele. It interacts with chromatin and may promote long-range DNA interactions that influence the regulation of gene expression. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant in the IGF1R gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: 4.6449 (above the threshold of 3.09). GenCC associations: The gene is linked to growth delay due to insulin-like growth factor I resistance.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22191292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1R	NM_000875.5	c.71C>G	p.Ser24Trp	missense_variant	Exon 1 of 21	ENST00000650285.1	NP_000866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1R	ENST00000650285.1	c.71C>G	p.Ser24Trp	missense_variant	Exon 1 of 21		NM_000875.5	ENSP00000497069.1
IGF1R	ENST00000559925.5	n.71C>G		non_coding_transcript_exon_variant	Exon 1 of 10	1
IGF1R	ENST00000649865.1	c.71C>G	p.Ser24Trp	missense_variant	Exon 1 of 21			ENSP00000496919.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246874 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134028

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1458442 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 725554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000602 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71C>G (p.S24W) alteration is located in exon 1 (coding exon 1) of the IGF1R gene. This alteration results from a C to G substitution at nucleotide position 71, causing the serine (S) at amino acid position 24 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	D;.;D;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.82	.;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N;.;N;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.73	.;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.070	.;.;T;T
Sift4G	Uncertain	0.023	.;.;D;D
Polyphen		0.29	B;P;B;P
Vest4		0.46, 0.41
MutPred		0.50		Gain of catalytic residue at S24 (P = 0.0576);Gain of catalytic residue at S24 (P = 0.0576);Gain of catalytic residue at S24 (P = 0.0576);Gain of catalytic residue at S24 (P = 0.0576);
MVP		0.74
MPC		1.2
ClinPred		0.22	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1013771934; hg19: chr15-99192881;