chr16-1790721-C-T

Position:

• chr16-1790721-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004970.3(IGFALS):​c.1697G>A​(p.Cys566Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 1,456,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: IGFALS NM_004970.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0820

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14807409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFALS	NM_004970.3	c.1697G>A	p.Cys566Tyr	missense_variant	2/2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2	c.1811G>A	p.Cys604Tyr	missense_variant	2/2		NP_001139478.1
IGFALS	NR_027389.1	n.1751G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFALS	ENST00000215539.4	c.1697G>A	p.Cys566Tyr	missense_variant	2/2	1	NM_004970.3	ENSP00000215539.3
IGFALS	ENST00000415638.3	c.1811G>A	p.Cys604Tyr	missense_variant	2/2	2		ENSP00000416683.3
SPSB3	ENST00000569769.1	c.-13+2916G>A		intron_variant		3		ENSP00000455098.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000893 AC: 13 AN: 1456370 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 724108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1697G>A (p.C566Y) alteration is located in exon 2 (coding exon 2) of the IGFALS gene. This alteration results from a G to A substitution at nucleotide position 1697, causing the cysteine (C) at amino acid position 566 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Short stature due to primary acid-labile subunit deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.7
DANN	Benign	0.79
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.61	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.049
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.033	D;D
Polyphen		0.58	P;.
Vest4		0.21
MutPred		0.52		Gain of catalytic residue at I565 (P = 0.0868);.;
MVP		0.35
MPC		0.13
ClinPred		0.19	T
GERP RS		-2.7
Varity_R		0.054
gMVP		0.72

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: rs1379588956; hg19: chr16-1840722;