rs533252393

Variant names:

• chr16-1790700-G-A
• rs533252393
• NM_004970.3:c.1718C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1790700-G-A
• chr16-1790700-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 16/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.374
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04800707).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFALS	NM_004970.3	MANE Select	c.1718C>T	p.Pro573Leu	missense	Exon 2 of 2	NP_004961.1	P35858-1
	IGFALS	NM_001146006.2		c.1832C>T	p.Pro611Leu	missense	Exon 2 of 2	NP_001139478.1	P35858-2
	IGFALS	NR_027389.1		n.1772C>T		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFALS	ENST00000215539.4	TSL:1 MANE Select	c.1718C>T	p.Pro573Leu	missense	Exon 2 of 2	ENSP00000215539.3	P35858-1
	IGFALS	ENST00000415638.3	TSL:2	c.1832C>T	p.Pro611Leu	missense	Exon 2 of 2	ENSP00000416683.3	P35858-2
	IGFALS	ENST00000897144.1		c.1793C>T	p.Pro598Leu	missense	Exon 3 of 3	ENSP00000567203.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152204 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000631 AC: 15 AN: 237658 AF XY: 0.0000540

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000281

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000343 AC: 50 AN: 1456198 Hom.: 0 Cov.: 30 AF XY: 0.0000359 AC XY: 26 AN XY: 724062

African (AFR) AF: 0.0000599 AC: 2 AN: 33398

American (AMR) AF: 0.000227 AC: 10 AN: 44080

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 25978

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39500

South Asian (SAS) AF: 0.0000938 AC: 8 AN: 85308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51782

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1110228

Other (OTH) AF: 0.0000332 AC: 2 AN: 60162

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74492

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.37	T
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	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.37
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.060
Sift	Benign	0.033	D
Sift4G	Benign	0.10	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	T
GERP RS		-0.45
Varity_R		0.063
gMVP		0.41
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs533252393; hg19: chr16-1840701;