rs9282731

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004970.3(IGFALS):c.1642C>T(p.Arg548Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,583,154 control chromosomes in the GnomAD database, including 2,959 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R548Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.076 ( 1372 hom., cov: 33)

Exomes 𝑓: 0.012 ( 1587 hom. )

Consequence

IGFALS
NM_004970.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.174

Publications

14 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]

IGFALS links:

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]

SPSB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00459978).

BP6

Variant 16-1790776-G-A is Benign according to our data. Variant chr16-1790776-G-A is described in ClinVar as Benign. ClinVar VariationId is 318235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFALS	NM_004970.3 link	c.1642C>T	p.Arg548Trp	missense_variant	Exon 2 of 2	ENST00000215539.4	NP_004961.1	P35858-1Q8TAY0
IGFALS	NM_001146006.2 link	c.1756C>T	p.Arg586Trp	missense_variant	Exon 2 of 2		NP_001139478.1	P35858-2Q8TAY0
IGFALS	NR_027389.1 link	n.1696C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGFALS	ENST00000215539.4 link	c.1642C>T	p.Arg548Trp	missense_variant	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3	P35858-1
IGFALS	ENST00000415638.3 link	c.1756C>T	p.Arg586Trp	missense_variant	Exon 2 of 2	2		ENSP00000416683.3	P35858-2
SPSB3	ENST00000569769.1 link	c.-13+2861C>T		intron_variant	Intron 1 of 4	3		ENSP00000455098.1	H3BP12

Frequencies

GnomAD3 genomes

AF:

0.0757

AC:

11511

AN:

152146

Hom.:

1368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0266

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0695

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.0511

GnomAD2 exomes

AF:

0.0295

AC:

5716

AN:

194064

AF XY:

0.0280

show subpopulations

Gnomad AFR exome

AF:

0.273

Gnomad AMR exome

AF:

0.0136

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0125

AC:

17881

AN:

1430892

Hom.:

1587

Cov.:

AF XY:

0.0136

AC XY:

9649

AN XY:

709394

show subpopulations

African (AFR)

AF:

0.268

AC:

8773

AN:

32770

American (AMR)

AF:

0.0152

AC:

599

AN:

39512

Ashkenazi Jewish (ASJ)

AF:

0.00102

AC:

AN:

25542

East Asian (EAS)

AF:

0.000928

AC:

AN:

37722

South Asian (SAS)

AF:

0.0745

AC:

6128

AN:

82286

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49786

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000716

AC:

786

AN:

1098320

Other (OTH)

AF:

0.0243

AC:

1438

AN:

59240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1096

2192

3289

4385

5481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

338

676

1014

1352

1690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0758

AC:

11548

AN:

152262

Hom.:

1372

Cov.:

AF XY:

0.0742

AC XY:

5527

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.255

AC:

10582

AN:

41496

American (AMR)

AF:

0.0266

AC:

407

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5184

South Asian (SAS)

AF:

0.0702

AC:

339

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68024

Other (OTH)

AF:

0.0510

AC:

108

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

463

926

1388

1851

2314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0161

Hom.:

509

Bravo

AF:

0.0844

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.238

AC:

1035

ESP6500EA

AF:

0.00164

AC:

ExAC

AF:

0.0311

AC:

3685

Asia WGS

AF:

0.0610

AC:

211

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

IGFALS-related disorder

Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Short stature due to primary acid-labile subunit deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.9

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.54

D;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.

PhyloP100

-0.17

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.051

Sift

Benign

0.10

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.40

B;.

Vest4

0.16

MPC

0.053

ClinPred

0.035

GERP RS

-2.2

Varity_R

0.081

gMVP

0.80

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over