16-1792208-A-G

Variant names:

• chr16-1792208-A-G
• rs3751893
• NM_004970.3:c.210T>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.210T>C​(p.Asp70Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,608,936 control chromosomes in the GnomAD database, including 526,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49797 hom., cov: 35)
  • Exomes 𝑓: 0.81 (476598 hom.)
• Consequence: IGFALS NM_004970.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.89

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 (MetaRNN=9.0638804E-7).
• BP6: Variant 16-1792208-A-G is Benign according to our data. Variant chr16-1792208-A-G is described in ClinVar as [Benign]. Clinvar id is 318265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1792208-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFALS	NM_004970.3	c.210T>C	p.Asp70Asp	synonymous_variant	Exon 2 of 2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2	c.324T>C	p.Asp108Asp	synonymous_variant	Exon 2 of 2		NP_001139478.1
IGFALS	NR_027389.1	n.264T>C		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.210T>C	p.Asp70Asp	synonymous_variant	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3
IGFALS	ENST00000568221.1	c.242T>C	p.Met81Thr	missense_variant	Exon 2 of 2	4		ENSP00000456923.1
IGFALS	ENST00000415638.3	c.324T>C	p.Asp108Asp	synonymous_variant	Exon 2 of 2	2		ENSP00000416683.3
SPSB3	ENST00000569769.1	c.-13+1429T>C		intron_variant	Intron 1 of 4	3		ENSP00000455098.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122827 AN: 152142 Hom.: 49752 Cov.: 35

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.850

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.828

GnomAD3 exomes AF: 0.798 AC: 188802 AN: 236560 Hom.: 75523 AF XY: 0.795 AC XY: 102814 AN XY: 129354

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.817

Gnomad ASJ exome AF: 0.850

Gnomad EAS exome AF: 0.749

Gnomad SAS exome AF: 0.752

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.820

Gnomad OTH exome AF: 0.802

GnomAD4 exome AF: 0.808 AC: 1177070 AN: 1456676 Hom.: 476598 Cov.: 73 AF XY: 0.806 AC XY: 583762 AN XY: 724614

Gnomad4 AFR exome AF: 0.833

Gnomad4 AMR exome AF: 0.811

Gnomad4 ASJ exome AF: 0.847

Gnomad4 EAS exome AF: 0.693

Gnomad4 SAS exome AF: 0.749

Gnomad4 FIN exome AF: 0.721

Gnomad4 NFE exome AF: 0.819

Gnomad4 OTH exome AF: 0.803

GnomAD4 genome AF: 0.807 AC: 122932 AN: 152260 Hom.: 49797 Cov.: 35 AF XY: 0.799 AC XY: 59482 AN XY: 74428

Gnomad4 AFR AF: 0.829

Gnomad4 AMR AF: 0.807

Gnomad4 ASJ AF: 0.850

Gnomad4 EAS AF: 0.723

Gnomad4 SAS AF: 0.763

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.829

Alfa AF: 0.820 Hom.: 56796

Bravo AF: 0.820

TwinsUK AF: 0.816 AC: 3024

ALSPAC AF: 0.814 AC: 3139

ESP6500AA AF: 0.816 AC: 3580

ESP6500EA AF: 0.822 AC: 7065

ExAC AF: 0.796 AC: 95593

Asia WGS AF: 0.723 AC: 2516 AN: 3478

EpiCase AF: 0.823

EpiControl AF: 0.827

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IGFALS-related disorder Benign:1

May 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.97	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.015
DANN	Benign	0.27
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	9.1e-7	T
PROVEAN	Pathogenic	-6.0	D
Vest4		0.066
GERP RS		-11

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: rs3751893; hg19: chr16-1842209; COSMIC: COSV51904911; COSMIC: COSV51904911;