chr16-1791784-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_004970.3(IGFALS):c.634G>A(p.Ala212Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,548,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A212V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

IGFALS
NM_004970.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.27

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031242609).

BP6

Variant 16-1791784-C-T is Benign according to our data. Variant chr16-1791784-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 318256.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000527 (736/1396078) while in subpopulation EAS AF = 0.00103 (37/36046). AF 95% confidence interval is 0.000766. There are 0 homozygotes in GnomAdExome4. There are 346 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFALS	NM_004970.3 link	c.634G>A	p.Ala212Thr	missense_variant	Exon 2 of 2	ENST00000215539.4	NP_004961.1	P35858-1Q8TAY0
IGFALS	NM_001146006.2 link	c.748G>A	p.Ala250Thr	missense_variant	Exon 2 of 2		NP_001139478.1	P35858-2Q8TAY0
IGFALS	NR_027389.1 link	n.688G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGFALS	ENST00000215539.4 link	c.634G>A	p.Ala212Thr	missense_variant	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3	P35858-1
IGFALS	ENST00000415638.3 link	c.748G>A	p.Ala250Thr	missense_variant	Exon 2 of 2	2		ENSP00000416683.3	P35858-2
SPSB3	ENST00000569769.1 link	c.-13+1853G>A		intron_variant	Intron 1 of 4	3		ENSP00000455098.1	H3BP12
IGFALS	ENST00000568221.1 link	c.*270G>A		downstream_gene_variant		4		ENSP00000456923.1	H3BSX8

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000378

AC:

AN:

147970

AF XY:

0.000313

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00202

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000505

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.000527

AC:

736

AN:

1396078

Hom.:

Cov.:

AF XY:

0.000502

AC XY:

346

AN XY:

689804

show subpopulations

African (AFR)

AF:

0.000220

AC:

AN:

31802

American (AMR)

AF:

0.0000547

AC:

AN:

36530

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25206

East Asian (EAS)

AF:

0.00103

AC:

AN:

36046

South Asian (SAS)

AF:

0.0000877

AC:

AN:

79848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40858

Middle Eastern (MID)

AF:

0.000538

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.000602

AC:

651

AN:

1082106

Other (OTH)

AF:

0.000482

AC:

AN:

58108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000315

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41570

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000338

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000482

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 05, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.634G>A (p.A212T) 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 634, causing the alanine (A) at amino acid position 212 to be replaced by a threonine (T). 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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Jan 25, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Sep 05, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.56

N;.

PhyloP100

1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.17

Sift

Benign

0.34

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.73

P;.

Vest4

0.067

MVP

0.88

MPC

0.10

ClinPred

0.022

GERP RS

3.0

Varity_R

0.029

gMVP

0.31

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over