rs551618643

Variant names:

• chr16-1791591-T-C
• rs551618643
• NM_004970.3:c.827A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_004970.3(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 NM_004970.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.14

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]

ACMG classification

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 rank	MANE	Protein	UniProt
IGFALS	NM_004970.3	c.827A>G	p.Asn276Ser	missense_variant	Exon 2 of 2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2	c.941A>G	p.Asn314Ser	missense_variant	Exon 2 of 2		NP_001139478.1
IGFALS	NR_027389.1	n.881A>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFALS	ENST00000215539.4	c.827A>G	p.Asn276Ser	missense_variant	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3
IGFALS	ENST00000415638.3	c.941A>G	p.Asn314Ser	missense_variant	Exon 2 of 2	2		ENSP00000416683.3
SPSB3	ENST00000569769.1	c.-13+2046A>G		intron_variant	Intron 1 of 4	3		ENSP00000455098.1
IGFALS	ENST00000568221.1	c.*463A>G		downstream_gene_variant		4		ENSP00000456923.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152116 Hom.: 0 Cov.: 33

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: 10 AN: 170546 Hom.: 0 AF XY: 0.0000763 AC XY: 7 AN XY: 91792

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: 46 AN: 1412036 Hom.: 0 Cov.: 32 AF XY: 0.0000401 AC XY: 28 AN XY: 698528

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: 4 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74442

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.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000510 AC: 6

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short stature due to primary acid-labile subunit deficiency Pathogenic:2

Sep 27, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.73	T
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	D
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

Other links and lift over

dbSNP: rs551618643; hg19: chr16-1841592;