Genetic Variant IGFALS:p.Asp70Glu (chr16-1792208-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004970.3(IGFALS):c.210T>A(p.Asp70Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D70D) has been classified as Benign.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IGFALS
NM_004970.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.89

Publications

32 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056673676).

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.210T>A	p.Asp70Glu	missense	Exon 2 of 2	NP_004961.1	P35858-1
IGFALS	NM_001146006.2		c.324T>A	p.Asp108Glu	missense	Exon 2 of 2	NP_001139478.1	P35858-2
IGFALS	NR_027389.1		n.264T>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.210T>A	p.Asp70Glu	missense	Exon 2 of 2	ENSP00000215539.3	P35858-1
IGFALS	ENST00000415638.3	TSL:2	c.324T>A	p.Asp108Glu	missense	Exon 2 of 2	ENSP00000416683.3	P35858-2
IGFALS	ENST00000897144.1		c.285T>A	p.Asp95Glu	missense	Exon 3 of 3	ENSP00000567203.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1456760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724668

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111470

Other (OTH)

AF:

0.00

AC:

AN:

60280

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

98604

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.0010

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.39

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

PhyloP100

-2.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.23

REVEL

Benign

0.29

Sift

Benign

0.80

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.012

MutPred

0.26

Gain of helix (P = 0.1736)

MVP

0.70

MPC

0.048

ClinPred

0.034

GERP RS

-11

Varity_R

0.040

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over