rs2854746

chr7-45921046-G-Achr7-45921046-G-Cchr7-45921046-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000598.5(IGFBP3):c.95C>T(p.Ala32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000486 in 1,441,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059669197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGFBP3	NM_000598.5	c.95C>T	p.Ala32Val	missense_variant	1/5	ENST00000613132.5
IGFBP3	NM_001013398.2	c.95C>T	p.Ala32Val	missense_variant	1/5
IGFBP3	XM_047420325.1	c.95C>T	p.Ala32Val	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGFBP3	ENST00000613132.5	c.95C>T	p.Ala32Val	missense_variant	1/5	5	NM_000598.5	P4
IGFBP3	ENST00000381083.9	c.95C>T	p.Ala32Val	missense_variant	1/5	5		A1
IGFBP3	ENST00000381086.9	c.9+86C>T		intron_variant		2
IGFBP3	ENST00000448817.1	c.73+581C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000661 AC: 10 AN: 151250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 60 AN: 1289990 Hom.: 0 Cov.: 43 AF XY: 0.0000457 AC XY: 29 AN XY: 635014

Gnomad4 AFR exome AF: 0.0000786

Gnomad4 AMR exome AF: 0.0000930

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: 0.0000482

Gnomad4 OTH exome AF: 0.0000939

GnomAD4 genome AF: 0.0000661 AC: 10 AN: 151250 Hom.: 0 Cov.: 33 AF XY: 0.0000812 AC XY: 6 AN XY: 73878

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.26	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.022
Sift	Benign	0.54	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.071	B;.
Vest4		0.077
MutPred		0.22		Loss of relative solvent accessibility (P = 0.0981);Loss of relative solvent accessibility (P = 0.0981);
MVP		0.32
MPC		0.34
ClinPred		0.027	T
GERP RS		0.63
Varity_R		0.032
gMVP		0.42

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;