chr7-45915430-A-G

Variant names:

• chr7-45915430-A-G
• rs3110697
• NM_000598.5:c.751-485T>C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_000598.5(IGFBP3):c.751-485T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.574 (AC=95,454) in the gnomAD database across 166,420 control chromosomes, including 27,750 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.72. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (25507 hom., cov: 32)
  • Exomes 𝑓: 0.55 (2243 hom.)
• Consequence: IGFBP3 NM_000598.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.199
• Publications: 70 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7204 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IGFBP3 NM_000598.5	MANE Select	c.751-485T>C	intron	Intron 3 of 4	Prot: NP_000589.2 UniProt:
	IGFBP3 NM_001013398.2		c.769-485T>C	intron	Intron 3 of 4	Prot: NP_001013416.1 UniProt:

IGFBP3 NM_000598.5

MANE Select

HGVSc / HGVSpc.751-485T>C

Exon rankIntron 3 of 4

intron

Prot: NP_000589.2UniProt: P17936-1

IGFBP3 NM_001013398.2

HGVSc / HGVSpc.769-485T>C

Exon rankIntron 3 of 4

intron

Prot: NP_001013416.1UniProt: P17936-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IGFBP3 ENST00000613132.5	TSL:5MANE Select	c.751-485T>C	intron	Intron 3 of 4	Prot: ENSP00000477772.2 UniProt:
	IGFBP3 ENST00000908406.1		c.841-485T>C	intron	Intron 4 of 5	Prot: ENSP00000578465.1 UniProt:
	IGFBP3 ENST00000381083.9	TSL:5	c.769-485T>C	intron	Intron 3 of 4	Prot: ENSP00000370473.4 UniProt:

IGFBP3 ENST00000613132.5

TSL:5MANE Select

HGVSc / HGVSpc.751-485T>C

Exon rankIntron 3 of 4

intron

Prot: ENSP00000477772.2UniProt: P17936-1

IGFBP3 ENST00000908406.1

HGVSc / HGVSpc.841-485T>C

Exon rankIntron 4 of 5

intron

Prot: ENSP00000578465.1UniProt: A0ACI8RUV2

IGFBP3 ENST00000381083.9

TSL:5

HGVSc / HGVSpc.769-485T>C

Exon rankIntron 3 of 4

intron

Prot: ENSP00000370473.4UniProt: P17936-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.576	AC:87525	Hom:25503	AN:151924	Cov:32
GnomAD4 exome	AF: 0.549	AC:7887	Hom:2243	AN:14378	Cov:
GnomAD4 genome	AF: 0.576	AC:87567	Hom:25507	AN:152042	Cov:32
TOPMed (Bravo)	AF: 0.574	AC:151866	Hom:44528	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.578	AC:304756	Hom:88847	AN:527020	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.588	AC:1376	Hom:416	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.743	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.527	AC:158	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.559	AC:1945	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.746	AC:5394	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.460	AC:81	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.751	AC:92218	Hom:34621	AN:122804	Cov:
Turkish Variome	AF: 0.558	AC:862	Hom:239	AN:1546	Cov:
UK10K	AF: 0.582	AC:4404	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.754	AC:6760	Hom:2557	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0323	444	13754	0.0284	694	24432

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.37
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.44
GPN-Star LLR	N/A	0.48
GPN-Star score	N/A	-0.48
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.20

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3110697;

hg19: chr7-45955029;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar