chr7-45920741-G-A

Variant names:

• chr7-45920741-G-A
• rs1329955861
• NM_000598.5:c.400C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000598.5(IGFBP3):​c.400C>T​(p.Pro134Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000793 in 1,260,560 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: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

Genes affected

IGFBP3 (HGNC:5472): (insulin like growth factor binding protein 3) This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein forms a ternary complex with insulin-like growth factor acid-labile subunit (IGFALS) and either insulin-like growth factor (IGF) I or II. In this form, it circulates in the plasma, prolonging the half-life of IGFs and altering their interaction with cell surface receptors. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10530269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.400C>T	p.Pro134Ser	missense_variant	Exon 1 of 5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.400C>T	p.Pro134Ser	missense_variant	Exon 1 of 5		NP_001013416.1
IGFBP3	XM_047420325.1	c.400C>T	p.Pro134Ser	missense_variant	Exon 1 of 4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.400C>T	p.Pro134Ser	missense_variant	Exon 1 of 5	5	NM_000598.5	ENSP00000477772.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.93e-7 AC: 1 AN: 1260560 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 617992

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: 9.77e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.400C>T (p.P134S) alteration is located in exon 1 (coding exon 1) of the IGFBP3 gene. This alteration results from a C to T substitution at nucleotide position 400, causing the proline (P) at amino acid position 134 to be replaced by a serine (S). 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	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.022	T;T;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T;T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;M;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.54	N;.;N;N;.
REVEL	Benign	0.089
Sift	Benign	0.29	T;.;T;T;.
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.0030	B;.;B;.;.
Vest4		0.11
MutPred		0.18		.;.;Gain of phosphorylation at P134 (P = 0.016);Gain of phosphorylation at P134 (P = 0.016);.;
MVP		0.45
MPC		0.93
ClinPred		0.16	T
GERP RS		0.013
Varity_R		0.032
gMVP		0.35

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: rs1329955861; hg19: chr7-45960340;