4-57032426-C-A

Variant names:

• chr4-57032426-C-A
• NM_001553.3:c.829G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001553.3(IGFBP7):​c.829G>T​(p.Gly277Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000185 in 1,461,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G277S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: IGFBP7 NM_001553.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-57032426-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1252043.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP7	NM_001553.3	c.829G>T	p.Gly277Cys	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000295666.6	NP_001544.1
IGFBP7	NM_001253835.2	c.829G>T	p.Gly277Cys	missense_variant	Exon 4 of 4		NP_001240764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6	c.829G>T	p.Gly277Cys	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_001553.3	ENSP00000295666.4
IGFBP7	ENST00000514062.2	c.829G>T	p.Gly277Cys	missense_variant	Exon 4 of 4	2		ENSP00000486293.1
IGFBP7	ENST00000512512.3	n.469G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461372 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726984

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: 0.0000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.038	D;D
Polyphen		0.98	D;.
Vest4		0.27
MutPred		0.40		Gain of methylation at K276 (P = 0.0202);Gain of methylation at K276 (P = 0.0202);
MVP		0.67
MPC		1.0
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.19
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57898592;