NM_000598.5:c.95C>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000598.5(IGFBP3):​c.95C>G​(p.Ala32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,441,040 control chromosomes in the GnomAD database, including 118,622 homozygotes. 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. A32V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (11466 hom., cov: 33)
  • Exomes 𝑓: 0.40 (107156 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.1002727E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

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>G	p.Ala32Gly	missense	Exon 1 of 5	NP_000589.2	P17936-1
	IGFBP3	NM_001013398.2		c.95C>G	p.Ala32Gly	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>G	p.Ala32Gly	missense	Exon 1 of 5	ENSP00000477772.2	P17936-1
	IGFBP3	ENST00000908406.1		c.95C>G	p.Ala32Gly	missense	Exon 1 of 6	ENSP00000578465.1
	IGFBP3	ENST00000381083.9	TSL:5	c.95C>G	p.Ala32Gly	missense	Exon 1 of 5	ENSP00000370473.4	P17936-2

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57281 AN: 151182 Hom.: 11477 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.386

GnomAD2 exomes AF: 0.382 AC: 21599 AN: 56480 AF XY: 0.389

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.485

Gnomad EAS exome AF: 0.782

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.402 AC: 518243 AN: 1289750 Hom.: 107156 Cov.: 43 AF XY: 0.400 AC XY: 254181 AN XY: 634912

African (AFR) AF: 0.312 AC: 7932 AN: 25450

American (AMR) AF: 0.263 AC: 5658 AN: 21474

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 10010 AN: 21086

East Asian (EAS) AF: 0.761 AC: 20982 AN: 27554

South Asian (SAS) AF: 0.345 AC: 23488 AN: 68042

European-Finnish (FIN) AF: 0.349 AC: 11229 AN: 32146

Middle Eastern (MID) AF: 0.424 AC: 1615 AN: 3808

European-Non Finnish (NFE) AF: 0.401 AC: 415628 AN: 1036986

Other (OTH) AF: 0.408 AC: 21701 AN: 53204

GnomAD4 genome AF: 0.379 AC: 57274 AN: 151290 Hom.: 11466 Cov.: 33 AF XY: 0.377 AC XY: 27912 AN XY: 73960

African (AFR) AF: 0.311 AC: 12873 AN: 41388

American (AMR) AF: 0.320 AC: 4864 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1592 AN: 3464

East Asian (EAS) AF: 0.751 AC: 3832 AN: 5100

South Asian (SAS) AF: 0.361 AC: 1742 AN: 4822

European-Finnish (FIN) AF: 0.350 AC: 3603 AN: 10304

Middle Eastern (MID) AF: 0.479 AC: 139 AN: 290

European-Non Finnish (NFE) AF: 0.403 AC: 27294 AN: 67720

Other (OTH) AF: 0.383 AC: 805 AN: 2100

Alfa AF: 0.211 Hom.: 419

Bravo AF: 0.377

ExAC AF: 0.283 AC: 3944

Asia WGS AF: 0.484 AC: 1665 AN: 3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.9
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0000041	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.36
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.017
Sift	Benign	0.38	T
Sift4G	Benign	0.91	T
Polyphen		0.0060	B
Vest4		0.059
MPC		0.54
ClinPred		0.0019	T
GERP RS		0.63
PromoterAI		-0.16	Neutral
Varity_R		0.036
gMVP		0.43
Mutation Taster		=99/1	polymorphism (auto)

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; COSMIC: COSV51872757; COSMIC: COSV51872757;