4-57110078-T-G

Variant names:

• chr4-57110078-T-G
• rs777120470
• NM_001553.3:c.274A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001553.3(IGFBP7):​c.274A>C​(p.Lys92Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,404,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: IGFBP7 NM_001553.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.382

Genes affected

IGFBP7 (HGNC:5476): (insulin like growth factor binding protein 7) This gene encodes a member of the insulin-like growth factor (IGF)-binding protein (IGFBP) family. IGFBPs bind IGFs with high affinity, and regulate IGF availability in body fluids and tissues and modulate IGF binding to its receptors. This protein binds IGF-I and IGF-II with relatively low affinity, and belongs to a subfamily of low-affinity IGFBPs. It also stimulates prostacyclin production and cell adhesion. Alternatively spliced transcript variants encoding different isoforms have been described for this gene, and one variant has been associated with retinal arterial macroaneurysm (PMID:21835307). [provided by RefSeq, Dec 2011]

IGFBP7-AS1 (HGNC:40296): (IGFBP7 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2692349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP7	NM_001553.3	c.274A>C	p.Lys92Gln	missense_variant	Exon 1 of 5	ENST00000295666.6	NP_001544.1
IGFBP7	NM_001253835.2	c.274A>C	p.Lys92Gln	missense_variant	Exon 1 of 4		NP_001240764.1
IGFBP7-AS1	NR_034081.1	n.209+108T>G		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6	c.274A>C	p.Lys92Gln	missense_variant	Exon 1 of 5	1	NM_001553.3	ENSP00000295666.4
IGFBP7-AS1	ENST00000499667.6	n.209+108T>G		intron_variant	Intron 1 of 4	1
IGFBP7	ENST00000514062.2	c.274A>C	p.Lys92Gln	missense_variant	Exon 1 of 4	2		ENSP00000486293.1
IGFBP7-AS1	ENST00000508328.6	n.191+108T>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000631 AC: 1 AN: 158420 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 87680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000152

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 41 AN: 1404412 Hom.: 0 Cov.: 31 AF XY: 0.0000288 AC XY: 20 AN XY: 695302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000376

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000299 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.0075	T;.
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.23	N;.
REVEL	Benign	0.090
Sift	Benign	0.13	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.95	P;.
Vest4		0.16
MutPred		0.32		Loss of methylation at K92 (P = 0.0091);Loss of methylation at K92 (P = 0.0091);
MVP		0.64
MPC		1.1
ClinPred		0.38	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs777120470; hg19: chr4-57976244;