Genetic Variant IGFALS:p.Ala575Gly (chr16-1790694-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004970.3(IGFALS):c.1724C>G(p.Ala575Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,642 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A575V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IGFALS
NM_004970.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.555

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.099564284).

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.1724C>G	p.Ala575Gly	missense	Exon 2 of 2	NP_004961.1	P35858-1
IGFALS	NM_001146006.2		c.1838C>G	p.Ala613Gly	missense	Exon 2 of 2	NP_001139478.1	P35858-2
IGFALS	NR_027389.1		n.1778C>G		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.1724C>G	p.Ala575Gly	missense	Exon 2 of 2	ENSP00000215539.3	P35858-1
IGFALS	ENST00000415638.3	TSL:2	c.1838C>G	p.Ala613Gly	missense	Exon 2 of 2	ENSP00000416683.3	P35858-2
IGFALS	ENST00000897144.1		c.1799C>G	p.Ala600Gly	missense	Exon 3 of 3	ENSP00000567203.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455642

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

43978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00

AC:

AN:

85182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110004

Other (OTH)

AF:

0.00

AC:

AN:

60138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.80

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.12

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.55

M_CAP

Benign

0.059

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

0.56

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

REVEL

Benign

0.065

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.39

Vest4

0.076

MutPred

0.41

Loss of stability (P = 0.0761)

MVP

0.48

MPC

0.050

ClinPred

0.30

GERP RS

-4.0

Varity_R

0.14

gMVP

0.51

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