7-45921046-G-A

Variant names:

• chr7-45921046-G-A
• rs2854746
• NM_000598.5:c.95C>T

Variant summary

Our verdict is Likely benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 97 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000598.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP3	NM_000598.5	MANE Select	c.95C>T	p.Ala32Val	missense	Exon 1 of 5	NP_000589.2	P17936-1
	IGFBP3	NM_001013398.2		c.95C>T	p.Ala32Val	missense	Exon 1 of 5	NP_001013416.1	P17936-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP3	ENST00000613132.5	TSL:5 MANE Select	c.95C>T	p.Ala32Val	missense	Exon 1 of 5	ENSP00000477772.2	P17936-1
	IGFBP3	ENST00000908406.1		c.95C>T	p.Ala32Val	missense	Exon 1 of 6	ENSP00000578465.1
	IGFBP3	ENST00000381083.9	TSL:5	c.95C>T	p.Ala32Val	missense	Exon 1 of 5	ENSP00000370473.4	P17936-2

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 56480 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome 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

African (AFR) AF: 0.0000786 AC: 2 AN: 25456

American (AMR) AF: 0.0000930 AC: 2 AN: 21494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21092

East Asian (EAS) AF: 0.00 AC: 0 AN: 27562

South Asian (SAS) AF: 0.00 AC: 0 AN: 68084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32154

Middle Eastern (MID) AF: 0.000263 AC: 1 AN: 3808

European-Non Finnish (NFE) AF: 0.0000482 AC: 50 AN: 1037118

Other (OTH) AF: 0.0000939 AC: 5 AN: 53222

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41284

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67746

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 419

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.36
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.022
Sift	Benign	0.54	T
Sift4G	Benign	0.56	T
Polyphen		0.071	B
Vest4		0.077
MutPred		0.22		Loss of relative solvent accessibility (P = 0.0981)
MVP		0.32
MPC		0.34
ClinPred		0.027	T
GERP RS		0.63
PromoterAI		-0.20	Neutral
Varity_R		0.032
gMVP		0.42
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2854746; hg19: chr7-45960645;