rs17559

Positions:

chr16-1791032-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004970.3(IGFALS):c.1386C>T(p.Tyr462=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.71

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 -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/exons	MANE	Protein
IGFALS	NM_004970.3 linkuse as main transcript	c.1386C>T	p.Tyr462=	synonymous_variant	2/2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2 linkuse as main transcript	c.1500C>T	p.Tyr500=	synonymous_variant	2/2		NP_001139478.1
IGFALS	NR_027389.1 linkuse as main transcript	n.1440C>T		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.1386C>T	p.Tyr462=	synonymous_variant	2/2	1	NM_004970.3	ENSP00000215539	P1	P35858-1
IGFALS	ENST00000415638.3 linkuse as main transcript	c.1500C>T	p.Tyr500=	synonymous_variant	2/2	2		ENSP00000416683		P35858-2
SPSB3	ENST00000569769.1 linkuse as main transcript	c.-13+2605C>T		intron_variant		3		ENSP00000455098

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30343

AN:

152096

Hom.:

4912

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.126

AC XY:

90460

AN XY:

719756

show subpopulations

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.:

AF XY:

0.198

AC XY:

14699

AN XY:

74414

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2021	- -

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

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

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