rs17559

Variant names:

• chr16-1791032-G-A
• rs17559
• NM_004970.3:c.1386C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1791032-G-A
• chr16-1791032-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004970.3(IGFALS):​c.1386C>T​(p.Tyr462Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,598,232 control chromosomes in the GnomAD database, including 19,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4936 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14844 hom.)
• Consequence: IGFALS NM_004970.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.71

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-1791032-G-A is Benign according to our data. Variant chr16-1791032-G-A is described in ClinVar as [Benign]. Clinvar id is 318241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1791032-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFALS	NM_004970.3	c.1386C>T	p.Tyr462Tyr	synonymous_variant	Exon 2 of 2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2	c.1500C>T	p.Tyr500Tyr	synonymous_variant	Exon 2 of 2		NP_001139478.1
IGFALS	NR_027389.1	n.1440C>T		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.1386C>T	p.Tyr462Tyr	synonymous_variant	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3
IGFALS	ENST00000415638.3	c.1500C>T	p.Tyr500Tyr	synonymous_variant	Exon 2 of 2	2		ENSP00000416683.3
SPSB3	ENST00000569769.1	c.-13+2605C>T		intron_variant	Intron 1 of 4	3		ENSP00000455098.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30343 AN: 152096 Hom.: 4912 Cov.: 33

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.0685

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.144 AC: 33667 AN: 233094 Hom.: 3953 AF XY: 0.148 AC XY: 19036 AN XY: 128596

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.0668

Gnomad ASJ exome AF: 0.0887

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.321

Gnomad FIN exome AF: 0.0672

Gnomad NFE exome AF: 0.0940

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.121 AC: 175051 AN: 1446018 Hom.: 14844 Cov.: 33 AF XY: 0.126 AC XY: 90460 AN XY: 719756

Gnomad4 AFR exome AF: 0.457

Gnomad4 AMR exome AF: 0.0700

Gnomad4 ASJ exome AF: 0.0884

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.0709

Gnomad4 NFE exome AF: 0.0999

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.200 AC: 30425 AN: 152214 Hom.: 4936 Cov.: 33 AF XY: 0.198 AC XY: 14699 AN XY: 74414

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.0789

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.0685

Gnomad4 NFE AF: 0.0994

Gnomad4 OTH AF: 0.175

Alfa AF: 0.127 Hom.: 1110

Bravo AF: 0.207

Asia WGS AF: 0.270 AC: 939 AN: 3478

EpiCase AF: 0.0928

EpiControl AF: 0.0941

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.6
DANN	Benign	0.76

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: rs17559; hg19: chr16-1841033; COSMIC: COSV51904537; COSMIC: COSV51904537;