rs9282731

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:2

Conservation

PhyloP100: -0.174

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 made for transcript

Verdict is Benign. Variant got -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 id is 318235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1790776-G-A is described in Lovd as [Benign].

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/exons	MANE
IGFALS	NM_004970.3 linkuse as main transcript	c.1642C>T	p.Arg548Trp	missense_variant	2/2	ENST00000215539.4
IGFALS	NM_001146006.2 linkuse as main transcript	c.1756C>T	p.Arg586Trp	missense_variant	2/2
IGFALS	NR_027389.1 linkuse as main transcript	n.1696C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGFALS	ENST00000215539.4 linkuse as main transcript	c.1642C>T	p.Arg548Trp	missense_variant	2/2	1	NM_004970.3	P1	P35858-1
IGFALS	ENST00000415638.3 linkuse as main transcript	c.1756C>T	p.Arg586Trp	missense_variant	2/2	2			P35858-2
SPSB3	ENST00000569769.1 linkuse as main transcript	c.-13+2861C>T		intron_variant		3

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

GnomAD3 exomes

AF:

0.0295

AC:

5716

AN:

194064

Hom.:

492

AF XY:

0.0280

AC XY:

2943

AN XY:

105038

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 SAS exome

AF:

0.0794

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

Gnomad4 AFR exome

AF:

0.268

Gnomad4 AMR exome

AF:

0.0152

Gnomad4 ASJ exome

AF:

0.00102

Gnomad4 EAS exome

AF:

0.000928

Gnomad4 SAS exome

AF:

0.0745

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000716

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0758

AC:

11548

AN:

152262

Hom.:

1372

Cov.:

AF XY:

0.0742

AC XY:

5527

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.255

Gnomad4 AMR

AF:

0.0266

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0702

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00141

Gnomad4 OTH

AF:

0.0510

Alfa

AF:

0.0137

Hom.:

339

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

IGFALS-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

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

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;.

MutationTaster

Benign

0.99

P;P

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over