Genetic Variant NM_000598.5:c.750+97C>T (chr7-45916451-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000598.5(IGFBP3):c.750+97C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,295,998 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0085 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 12 hom. )

Consequence

IGFBP3
NM_000598.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.950

Publications

1 publications found

Variant links:

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]

IGFBP3 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00853 (1300/152338) while in subpopulation AFR AF = 0.03 (1246/41572). AF 95% confidence interval is 0.0286. There are 15 homozygotes in GnomAd4. There are 604 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
IGFBP3	NM_000598.5 link	c.750+97C>T	intron_variant	Intron 3 of 4	ENST00000613132.5	NP_000589.2	P17936-1B3KPF0
IGFBP3	NM_001013398.2 link	c.768+97C>T	intron_variant	Intron 3 of 4		NP_001013416.1	P17936-2
IGFBP3	XM_047420325.1 link	c.750+97C>T	intron_variant	Intron 3 of 3		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5 link	c.750+97C>T		intron_variant	Intron 3 of 4	5	NM_000598.5	ENSP00000477772.2		P17936-1A6XND0

Frequencies

GnomAD3 genomes

AF:

0.00853

AC:

1299

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00574

GnomAD4 exome

AF:

0.000838

AC:

958

AN:

1143660

Hom.:

AF XY:

0.000720

AC XY:

412

AN XY:

572012

show subpopulations

African (AFR)

AF:

0.0278

AC:

753

AN:

27128

American (AMR)

AF:

0.00142

AC:

AN:

40702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20922

East Asian (EAS)

AF:

0.00

AC:

AN:

35874

South Asian (SAS)

AF:

0.0000279

AC:

AN:

71650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45250

Middle Eastern (MID)

AF:

0.000574

AC:

AN:

3486

European-Non Finnish (NFE)

AF:

0.0000329

AC:

AN:

850338

Other (OTH)

AF:

0.00238

AC:

115

AN:

48310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00853

AC:

1300

AN:

152338

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

604

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0300

AC:

1246

AN:

41572

American (AMR)

AF:

0.00242

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68040

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

138

208

277

346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00728

Hom.:

Bravo

AF:

0.00967

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.1

(source)

DANN

Benign

0.47

PhyloP100

0.95

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over