chr16-1790700-G-A

Position:

chr16-1790700-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004970.3(IGFALS):c.1718C>T(p.Pro573Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,608,520 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

IGFALS
NM_004970.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.374

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04800707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IGFALS	NM_004970.3 linkuse as main transcript	c.1718C>T	p.Pro573Leu	missense_variant	2/2	ENST00000215539.4
IGFALS	NM_001146006.2 linkuse as main transcript	c.1832C>T	p.Pro611Leu	missense_variant	2/2
IGFALS	NR_027389.1 linkuse as main transcript	n.1772C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGFALS	ENST00000215539.4 linkuse as main transcript	c.1718C>T	p.Pro573Leu	missense_variant	2/2	1	NM_004970.3	P1	P35858-1
IGFALS	ENST00000415638.3 linkuse as main transcript	c.1832C>T	p.Pro611Leu	missense_variant	2/2	2			P35858-2
SPSB3	ENST00000569769.1 linkuse as main transcript	c.-13+2937C>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000631

AC:

AN:

237658

Hom.:

AF XY:

0.0000540

AC XY:

AN XY:

129510

show subpopulations

Gnomad AFR exome

AF:

0.0000679

Gnomad AMR exome

AF:

0.000179

Gnomad ASJ exome

AF:

0.000206

Gnomad EAS exome

AF:

0.0000562

Gnomad SAS exome

AF:

0.0000679

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000281

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000343

AC:

AN:

1456198

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

724062

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000938

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.1718C>T (p.P573L) alteration is located in exon 2 (coding exon 2) of the IGFALS gene. This alteration results from a C to T substitution at nucleotide position 1718, causing the proline (P) at amino acid position 573 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.4

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.060

Sift

Benign

0.033

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.0020

B;.

Vest4

0.13

MutPred

0.47

Gain of sheet (P = 0.0477);.;

MVP

0.59

MPC

0.050

ClinPred

0.032

GERP RS

-0.45

Varity_R

0.063

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over