15-98957104-A-T

Position:

• chr15-98957104-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000875.5(IGF1R):​c.3766A>T​(p.Arg1256Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1256S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0350

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 Pathogenic. Variant got 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.3766A>T	p.Arg1256Trp	missense_variant	21/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.3766A>T	p.Arg1256Trp	missense_variant	21/21		NM_000875.5	P4
SYNM-AS1	ENST00000559468.1	n.349-2716T>A		intron_variant, non_coding_transcript_variant		4
IGF1R	ENST00000649865.1	c.3763A>T	p.Arg1255Trp	missense_variant	21/21			A1
IGF1R	ENST00000558751.1	n.360A>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

GeneDx

Sep 08, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.5	.;.;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.91, 0.90
MutPred		0.87		Loss of disorder (P = 0.0139);.;Loss of disorder (P = 0.0139);.;
MVP		0.98
MPC		0.37
ClinPred		1.0	D
GERP RS		-11
Varity_R		0.80
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr15-99500333;