7-45921046-G-T

Position:

• chr7-45921046-G-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.95C>A​(p.Ala32Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,289,992 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A32G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359

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=0.10386106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.95C>A	p.Ala32Glu	missense_variant	1/5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.95C>A	p.Ala32Glu	missense_variant	1/5		NP_001013416.1
IGFBP3	XM_047420325.1	c.95C>A	p.Ala32Glu	missense_variant	1/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.95C>A	p.Ala32Glu	missense_variant	1/5	5	NM_000598.5	ENSP00000477772.2
IGFBP3	ENST00000381083.9	c.95C>A	p.Ala32Glu	missense_variant	1/5	5		ENSP00000370473.4
IGFBP3	ENST00000381086.9	c.9+86C>A		intron_variant		2		ENSP00000370476.4
IGFBP3	ENST00000448817.1	c.73+581C>A		intron_variant		4		ENSP00000389668.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.75e-7 AC: 1 AN: 1289992 Hom.: 0 Cov.: 43 AF XY: 0.00000157 AC XY: 1 AN XY: 635016

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: 0.00

Gnomad4 OTH exome AF: 0.0000188

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.058
Sift	Benign	0.27	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.94	P;.
Vest4		0.11
MutPred		0.23		Gain of solvent accessibility (P = 0.0246);Gain of solvent accessibility (P = 0.0246);
MVP		0.43
MPC		0.40
ClinPred		0.15	T
GERP RS		0.63
Varity_R		0.062
gMVP		0.49

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: rs2854746; hg19: chr7-45960645;