chr12-102419637-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000618.5(IGF1):c.274G>A(p.Val92Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IGF1
NM_000618.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.50

Publications

6 publications found

Variant links:

Genes affected

IGF1 (HGNC:5464): (insulin like growth factor 1) The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Sep 2015]

IGF1 links:

LINC02456 (HGNC:53389): (long intergenic non-protein coding RNA 2456)

LINC02456 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 12-102419637-C-T is Pathogenic according to our data. Variant chr12-102419637-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14789.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGF1	NM_000618.5 link	c.274G>A	p.Val92Met	missense_variant	Exon 3 of 4	ENST00000337514.11	NP_000609.1	P05019-2Q5U743Q59GC5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGF1	ENST00000337514.11 link	c.274G>A	p.Val92Met	missense_variant	Exon 3 of 4	1	NM_000618.5	ENSP00000337612.7		P05019-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461338

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Oct 12, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: reduced binding affinity of IGF1 to the IGF1-receptor with reduced IGF1-receptor autophosphorylation/activation (Walenkamp et al., 2005; Denley et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as V44M; This variant is associated with the following publications: (PMID: 25680077, 26034074, 29311900, 31416218, 21845174, 28149264, 31456057, 31736316, 22587301, 23392101, 22654835, 17785692, 34680948, 15576456, 22218435, 15769976, 34440832, 36546343) -

Oct 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 92 of the IGF1 protein (p.Val92Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with insulin-like growth factor I (IGF1) deficiency (PMID: 15769976). ClinVar contains an entry for this variant (Variation ID: 14789). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects IGF1 function (PMID: 15769976). 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. -

Growth delay due to insulin-like growth factor type 1 deficiency

Pathogenic:1

May 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

.;.;.;.;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;.;D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.5

M;M;M;.;M;M

PhyloP100

7.5

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.8

D;D;.;D;.;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;.;D;.;D

Sift4G

Uncertain

0.0070

D;D;.;D;.;D

Polyphen

1.0

.;.;.;.;.;D

Vest4

0.92

MutPred

0.87

Gain of disorder (P = 0.0308);Gain of disorder (P = 0.0308);Gain of disorder (P = 0.0308);.;Gain of disorder (P = 0.0308);Gain of disorder (P = 0.0308);

MVP

0.93

MPC

1.9

ClinPred

0.99

GERP RS

5.8

Varity_R

0.88

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over