16-1790700-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004970.3(IGFALS):​c.1718C>A​(p.Pro573Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. P573L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IGFALS
NM_004970.3 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.374

Publications

0 publications found
Variant links:
Genes affected
IGFALS (HGNC:5468): (insulin like growth factor binding protein acid labile subunit) The protein encoded by this gene is a serum protein that binds insulin-like growth factors, increasing their half-life and their vascular localization. Production of the encoded protein, which contains twenty leucine-rich repeats, is stimulated by growth hormone. Defects in this gene are a cause of acid-labile subunit deficiency, which maifests itself in a delayed and slow puberty. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
SPSB3 (HGNC:30629): (splA/ryanodine receptor domain and SOCS box containing 3) Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12435168).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IGFALSNM_004970.3 linkc.1718C>A p.Pro573Gln missense_variant Exon 2 of 2 ENST00000215539.4 NP_004961.1 P35858-1Q8TAY0
IGFALSNM_001146006.2 linkc.1832C>A p.Pro611Gln missense_variant Exon 2 of 2 NP_001139478.1 P35858-2Q8TAY0
IGFALSNR_027389.1 linkn.1772C>A non_coding_transcript_exon_variant Exon 2 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IGFALSENST00000215539.4 linkc.1718C>A p.Pro573Gln missense_variant Exon 2 of 2 1 NM_004970.3 ENSP00000215539.3 P35858-1
IGFALSENST00000415638.3 linkc.1832C>A p.Pro611Gln missense_variant Exon 2 of 2 2 ENSP00000416683.3 P35858-2
SPSB3ENST00000569769.1 linkc.-13+2937C>A intron_variant Intron 1 of 4 3 ENSP00000455098.1 H3BP12

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
237658
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1456198
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
724062
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33398
American (AMR)
AF:
0.00
AC:
0
AN:
44080
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25978
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39500
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85308
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51782
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
9.01e-7
AC:
1
AN:
1110228
Other (OTH)
AF:
0.00
AC:
0
AN:
60162
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
6.8
DANN
Benign
0.92
DEOGEN2
Benign
0.20
T;.
Eigen
Benign
-0.89
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.55
T;T
M_CAP
Benign
0.052
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L;.
PhyloP100
0.37
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.073
Sift
Uncertain
0.025
D;D
Sift4G
Benign
0.10
T;T
Polyphen
0.45
B;.
Vest4
0.28
MutPred
0.38
Loss of catalytic residue at P573 (P = 0.062);.;
MVP
0.68
MPC
0.081
ClinPred
0.42
T
GERP RS
-0.45
Varity_R
0.082
gMVP
0.41

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

Other links and lift over

dbSNP: rs533252393; hg19: chr16-1840701; API