7-45921130-G-A

Position:

• chr7-45921130-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000598.5(IGFBP3):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000371 in 1,347,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 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: 0.0000037 (0 hom.)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.114

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=0.00968126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.11C>T	p.Ala4Val	missense_variant	1/5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.11C>T	p.Ala4Val	missense_variant	1/5		NP_001013416.1
IGFBP3	XM_047420325.1	c.11C>T	p.Ala4Val	missense_variant	1/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.11C>T	p.Ala4Val	missense_variant	1/5	5	NM_000598.5	ENSP00000477772.2
IGFBP3	ENST00000381083.9	c.11C>T	p.Ala4Val	missense_variant	1/5	5		ENSP00000370473.4
IGFBP3	ENST00000381086.9	c.9+2C>T		splice_donor_variant, intron_variant		2		ENSP00000370476.4
IGFBP3	ENST00000448817.1	c.73+497C>T		intron_variant		4		ENSP00000389668.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000371 AC: 5 AN: 1347488 Hom.: 0 Cov.: 34 AF XY: 0.00000752 AC XY: 5 AN XY: 664768

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: 9.41e-7

Gnomad4 OTH exome AF: 0.0000714

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.11C>T (p.A4V) 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 11, causing the alanine (A) at amino acid position 4 to be replaced by a valine (V). 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	0.15
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.91
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.075	D
ClinPred		0.26	T
GERP RS		2.5

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: chr7-45960729;