7-45921046-G-A

Variant names:

• chr7-45921046-G-A
• rs2854746
• NM_000598.5:c.95C>T
• IGFBP3 p.Ala32Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

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 cumulative frequency of 0.0000486 (AC=70) in the gnomAD database across 1,441,240 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000693. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review 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: 21 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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000693 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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.95C>T p.Ala32Val	missense	Exon 1 of 5	Prot: NP_000589.2 UniProt:
	IGFBP3 NM_001013398.2		c.95C>T p.Ala32Val	missense	Exon 1 of 5	Prot: NP_001013416.1 UniProt:

IGFBP3 NM_000598.5

MANE Select

HGVSc / HGVSpc.95C>Tp.Ala32Val

Exon rankExon 1 of 5

missense

Prot: NP_000589.2UniProt: P17936-1

IGFBP3 NM_001013398.2

HGVSc / HGVSpc.95C>Tp.Ala32Val

Exon rankExon 1 of 5

missense

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.95C>T p.Ala32Val	missense	Exon 1 of 5	Prot: ENSP00000477772.2 UniProt:
	IGFBP3 ENST00000908406.1		c.95C>T p.Ala32Val	missense	Exon 1 of 6	Prot: ENSP00000578465.1 UniProt:
	IGFBP3 ENST00000381083.9	TSL:5	c.95C>T p.Ala32Val	missense	Exon 1 of 5	Prot: ENSP00000370473.4 UniProt:

IGFBP3 ENST00000613132.5

TSL:5MANE Select

HGVSc / HGVSpc.95C>Tp.Ala32Val

Exon rankExon 1 of 5

missense

Prot: ENSP00000477772.2UniProt: P17936-1

IGFBP3 ENST00000908406.1

HGVSc / HGVSpc.95C>Tp.Ala32Val

Exon rankExon 1 of 6

missense

Prot: ENSP00000578465.1UniProt: A0ACI8RUV2

IGFBP3 ENST00000381083.9

TSL:5

HGVSc / HGVSpc.95C>Tp.Ala32Val

Exon rankExon 1 of 5

missense

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000661	AC:10	Hom:0	AN:151250	Cov:33
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:56480	Cov:
GnomAD4 exome	AF: 0.0000465	AC:60	Hom:0	AN:1289990	Cov:43
GnomAD4 genome	AF: 0.0000661	AC:10	Hom:0	AN:151250	Cov:33
TOPMed (Bravo)	AF: 0.0000491	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:579	AN:15733	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122448	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.000656	85	129518	0.000401	85	211738

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	Uncertain	17
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
FuncVEP CTI	Benign	0.0053
GPN-Star LLR	N/A	-2.9
GPN-Star score	N/A	2.9
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.99	T
Mutation Taster	N/A	99/1	polymorphism
MutationAssessor	Benign	0.26	N
PhyloP100	Benign	0.36
popEVE	Benign	-3.0
PrimateAI	Pathogenic	0.86	D
PromoterAI	N/A	-0.20	Neutral
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.022
Sift	Benign	0.54	T
Sift4G	Benign	0.56	T
Varity_R	N/A	0.032
VESM-3B	Benign	-4.4

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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: rs2854746;

hg19: chr7-45960645;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar