NM_001553.3:c.829G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

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

Scores

1
7
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.74
Variant links:
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]

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ACMG classification

Classification made for transcript

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
IGFBP7NM_001553.3 linkc.829G>T p.Gly277Cys missense_variant, splice_region_variant Exon 4 of 5 ENST00000295666.6 NP_001544.1 Q16270-1
IGFBP7NM_001253835.2 linkc.829G>T p.Gly277Cys missense_variant Exon 4 of 4 NP_001240764.1 Q16270-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IGFBP7ENST00000295666.6 linkc.829G>T p.Gly277Cys missense_variant, splice_region_variant Exon 4 of 5 1 NM_001553.3 ENSP00000295666.4 Q16270-1
IGFBP7ENST00000514062.2 linkc.829G>T p.Gly277Cys missense_variant Exon 4 of 4 2 ENSP00000486293.1 Q16270-2
IGFBP7ENST00000512512.3 linkn.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
show subpopulations
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; API