chr17-40443853-C-T

Variant names:

• chr17-40443853-C-T
• rs578013057
• NM_001552.3:c.118C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001552.3(IGFBP4):​c.118C>T​(p.Pro40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,531,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IGFBP4 NM_001552.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

Genes affected

IGFBP4 (HGNC:5473): (insulin like growth factor binding protein 4) 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 binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33809692).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001552.3. 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
	IGFBP4	NM_001552.3	MANE Select	c.118C>T	p.Pro40Ser	missense	Exon 1 of 4	NP_001543.2	P22692-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP4	ENST00000269593.5	TSL:1 MANE Select	c.118C>T	p.Pro40Ser	missense	Exon 1 of 4	ENSP00000269593.4	P22692-1
	IGFBP4	ENST00000941634.1		c.118C>T	p.Pro40Ser	missense	Exon 1 of 4	ENSP00000611693.1
	IGFBP4	ENST00000906679.1		c.118C>T	p.Pro40Ser	missense	Exon 1 of 4	ENSP00000576738.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1379644 Hom.: 0 Cov.: 34 AF XY: 0.00000294 AC XY: 2 AN XY: 680922

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30986

American (AMR) AF: 0.00 AC: 0 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24962

East Asian (EAS) AF: 0.00 AC: 0 AN: 35512

South Asian (SAS) AF: 0.00 AC: 0 AN: 78920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077458

Other (OTH) AF: 0.00 AC: 0 AN: 57532

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000584 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.022
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.091
Sift	Benign	0.061	T
Sift4G	Benign	0.53	T
Polyphen		0.27	B
Vest4		0.19
MutPred		0.65		Gain of phosphorylation at P40 (P = 0.0191)
MVP		0.74
MPC		0.76
ClinPred		0.31	T
GERP RS		2.8
PromoterAI		-0.29	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.56

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: rs578013057; hg19: chr17-38600105;