rs551618643

Positions:

chr16-1791591-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The ENST00000215539.4(IGFALS):c.827A>G(p.Asn276Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000032 in 1,564,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

IGFALS
ENST00000215539.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.14

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 Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

PP5

Variant 16-1791591-T-C is Pathogenic according to our data. Variant chr16-1791591-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 318251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1791591-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IGFALS	NM_004970.3 linkuse as main transcript	c.827A>G	p.Asn276Ser	missense_variant	2/2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2 linkuse as main transcript	c.941A>G	p.Asn314Ser	missense_variant	2/2		NP_001139478.1
IGFALS	NR_027389.1 linkuse as main transcript	n.881A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFALS	ENST00000215539.4 linkuse as main transcript	c.827A>G	p.Asn276Ser	missense_variant	2/2	1	NM_004970.3	ENSP00000215539	P1	P35858-1
IGFALS	ENST00000415638.3 linkuse as main transcript	c.941A>G	p.Asn314Ser	missense_variant	2/2	2		ENSP00000416683		P35858-2
SPSB3	ENST00000569769.1 linkuse as main transcript	c.-13+2046A>G		intron_variant		3		ENSP00000455098

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000586

AC:

AN:

170546

Hom.:

AF XY:

0.0000763

AC XY:

AN XY:

91792

show subpopulations

Gnomad AFR exome

AF:

0.000103

Gnomad AMR exome

AF:

0.000114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000123

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000430

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000326

AC:

AN:

1412036

Hom.:

Cov.:

AF XY:

0.0000401

AC XY:

AN XY:

698528

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.000107

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000821

Gnomad4 SAS exome

AF:

0.000173

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000165

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000510

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Short stature due to primary acid-labile subunit deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	Across three studies, the IGFALS c.941A>G (p.Asn314Ser) variant, also referred to as c.827A>G (p.Asn276Ser), was reported in a total of four patients with acid-labile subunit (ALS) deficiency or short stature, including two homozygotes and two compound heterozygotes. The variant was also identified in a heterozygous state in three unaffected family members (Heath et al. 2008; Fafanova-Gambetti et al. 2010; Domene et al. 2013). The variant was absent from 200 control chromosomes but found in a heterozygous state in one of 188 normal-height children. The variant is reported at a frequency of 0.00012 in the total population of the Exome Aggregation Consortium. The Asn314 residue is highly conserved. Structural modeling by David et al. (2012) suggests the p.Asn314Ser variant may cause the loss of a hydrogen bond that normally stabilizes the IGFALS protein core structure. Martucci et al. (2016) expressed the p.Asn314Ser variant protein in CHO cells and found a complete lack of protein expression in cell lysates and media. Based on the evidence, the p.Asn314Ser variant is classified as likely pathogenic for acid-labile subunit deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.085

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.081

T;T

Polyphen

1.0

D;.

Vest4

0.90

MVP

0.95

MPC

0.31

ClinPred

0.78

GERP RS

4.1

Varity_R

0.80

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