chr16-1790710-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_004970.3(IGFALS):c.1708G>A(p.Asp570Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,608,640 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00078 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

IGFALS
NM_004970.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.42

Publications

4 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=0.02810356).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000781 (119/152316) while in subpopulation NFE AF = 0.0014 (95/68012). AF 95% confidence interval is 0.00117. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004970.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGFALS	NM_004970.3	MANE Select	c.1708G>A	p.Asp570Asn	missense	Exon 2 of 2	NP_004961.1	P35858-1
IGFALS	NM_001146006.2		c.1822G>A	p.Asp608Asn	missense	Exon 2 of 2	NP_001139478.1	P35858-2
IGFALS	NR_027389.1		n.1762G>A		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGFALS	ENST00000215539.4	TSL:1 MANE Select	c.1708G>A	p.Asp570Asn	missense	Exon 2 of 2	ENSP00000215539.3	P35858-1
IGFALS	ENST00000415638.3	TSL:2	c.1822G>A	p.Asp608Asn	missense	Exon 2 of 2	ENSP00000416683.3	P35858-2
IGFALS	ENST00000897144.1		c.1783G>A	p.Asp595Asn	missense	Exon 3 of 3	ENSP00000567203.1

Frequencies

GnomAD3 genomes

AF:

0.000782

AC:

119

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000769

AC:

183

AN:

237990

AF XY:

0.000779

show subpopulations

Gnomad AFR exome

AF:

0.000136

Gnomad AMR exome

AF:

0.000357

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000224

Gnomad FIN exome

AF:

0.000152

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00154

AC:

2246

AN:

1456324

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1085

AN XY:

724146

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33414

American (AMR)

AF:

0.000431

AC:

AN:

44088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.000203

AC:

AN:

39500

South Asian (SAS)

AF:

0.00

AC:

AN:

85344

European-Finnish (FIN)

AF:

0.0000965

AC:

AN:

51798

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00190

AC:

2110

AN:

1110256

Other (OTH)

AF:

0.00156

AC:

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

140

280

419

559

699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.000781

AC:

119

AN:

152316

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41578

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00113

Hom.:

Bravo

AF:

0.000827

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000754

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Short stature due to primary acid-labile subunit deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.2

PhyloP100

7.4

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.44

MVP

0.90

MPC

0.24

ClinPred

0.28

GERP RS

4.2

Varity_R

0.27

gMVP

0.47

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over