15-98957089-T-C

Position:

• chr15-98957089-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000875.5(IGF1R):​c.3751T>C​(p.Tyr1251His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y1251Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

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]

SYNM-AS1 (HGNC:55421): (SYNM antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Protein kinase (size 275) in uniprot entity IGF1R_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000875.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGF1R. . Trascript score misZ 4.6449 (greater than threshold 3.09). GenCC has associacion of gene with growth delay due to insulin-like growth factor I resistance.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.3751T>C	p.Tyr1251His	missense_variant	21/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.3751T>C	p.Tyr1251His	missense_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1	n.349-2701A>G		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.3748T>C	p.Tyr1250His	missense_variant	21/21			A1
IGF1R	ENST00000558751.1	n.345T>C		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with IGF1R-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1251 of the IGF1R protein (p.Tyr1251His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;D;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	.;.;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.20	N;.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	.;.;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.45	.;.;T;T
Sift4G	Benign	0.74	.;.;T;T
Polyphen		0.0020	B;D;B;D
Vest4		0.59, 0.58
MutPred		0.38		Gain of disorder (P = 0.0339);.;Gain of disorder (P = 0.0339);.;
MVP		0.90
MPC		0.40
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-99500318;