chr7-45917447-C-T

Variant names:

• chr7-45917447-C-T
• rs149155055
• NM_000598.5:c.404-8G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000598.5(IGFBP3):​c.404-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000886 in 1,597,740 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (6 hom.)
• Consequence: IGFBP3 NM_000598.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003352
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.376
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-45917447-C-T is Benign according to our data. Variant chr7-45917447-C-T is described in ClinVar as Benign. ClinVar VariationId is 792074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00459 (699/152170) while in subpopulation AFR AF = 0.0161 (668/41502). AF 95% confidence interval is 0.0151. There are 7 homozygotes in GnomAd4. There are 324 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 gene

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.404-8G>A		splice_region intron	N/A	NP_000589.2	P17936-1
	IGFBP3	NM_001013398.2		c.422-8G>A		splice_region intron	N/A	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.404-8G>A		splice_region intron	N/A	ENSP00000477772.2	P17936-1
	IGFBP3	ENST00000908406.1		c.404-8G>A		splice_region intron	N/A	ENSP00000578465.1
	IGFBP3	ENST00000381083.9	TSL:5	c.422-8G>A		splice_region intron	N/A	ENSP00000370473.4	P17936-2

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152052 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.00478

GnomAD2 exomes AF: 0.00131 AC: 313 AN: 238622 AF XY: 0.00102

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.0000646

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.000495 AC: 716 AN: 1445570 Hom.: 6 Cov.: 29 AF XY: 0.000439 AC XY: 315 AN XY: 717614

African (AFR) AF: 0.0180 AC: 595 AN: 33016

American (AMR) AF: 0.000648 AC: 28 AN: 43240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.000107 AC: 9 AN: 83922

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52906

Middle Eastern (MID) AF: 0.000540 AC: 3 AN: 5556

European-Non Finnish (NFE) AF: 0.0000200 AC: 22 AN: 1102714

Other (OTH) AF: 0.000972 AC: 58 AN: 59696

GnomAD4 genome AF: 0.00459 AC: 699 AN: 152170 Hom.: 7 Cov.: 32 AF XY: 0.00436 AC XY: 324 AN XY: 74390

African (AFR) AF: 0.0161 AC: 668 AN: 41502

American (AMR) AF: 0.00111 AC: 17 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00510

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.9
DANN	Benign	0.47
PhyloP100		0.38
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.020
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: rs149155055; hg19: chr7-45957046;