dbSNP rs368097770: IGFALS:p.Ala212Pro (chr16-1791784-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004970.3(IGFALS):c.634G>C(p.Ala212Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

IGFALS
NM_004970.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.27

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15268573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFALS	NM_004970.3 link	c.634G>C	p.Ala212Pro	missense_variant	Exon 2 of 2	ENST00000215539.4	NP_004961.1	P35858-1Q8TAY0
IGFALS	NM_001146006.2 link	c.748G>C	p.Ala250Pro	missense_variant	Exon 2 of 2		NP_001139478.1	P35858-2Q8TAY0
IGFALS	NR_027389.1 link	n.688G>C		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>C	p.Ala212Pro	missense_variant	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3	P35858-1
IGFALS	ENST00000415638.3 link	c.748G>C	p.Ala250Pro	missense_variant	Exon 2 of 2	2		ENSP00000416683.3	P35858-2
SPSB3	ENST00000569769.1 link	c.-13+1853G>C		intron_variant	Intron 1 of 4	3		ENSP00000455098.1	H3BP12
IGFALS	ENST00000568221.1 link	c.*270G>C		downstream_gene_variant		4		ENSP00000456923.1	H3BSX8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396080

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689804

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.081

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.73

N;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.076

Sift

Benign

0.32

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0030

B;.

Vest4

0.092

MutPred

0.38

Gain of catalytic residue at P211 (P = 0.0133);.;

MVP

0.89

MPC

0.065

ClinPred

0.17

GERP RS

3.0

Varity_R

0.076

gMVP

0.73

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over