Genetic Variant NM_004970.3:c.583_591dupAGCCTGCGC (chr16-1791826-C-CGCGCAGGCT) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM4PP5

The NM_004970.3(IGFALS):c.583_591dupAGCCTGCGC(p.Arg197_Glu198insSerLeuArg) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000361 in 1,549,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

IGFALS
NM_004970.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -1.94

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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_004970.3.

PP5

Variant 16-1791826-C-CGCGCAGGCT is Pathogenic according to our data. Variant chr16-1791826-C-CGCGCAGGCT is described in ClinVar as Pathogenic. ClinVar VariationId is 8129.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IGFALS	NM_004970.3 link	c.583_591dupAGCCTGCGC	p.Arg197_Glu198insSerLeuArg	conservative_inframe_insertion	Exon 2 of 2	ENST00000215539.4	NP_004961.1
IGFALS	NM_001146006.2 link	c.697_705dupAGCCTGCGC	p.Arg235_Glu236insSerLeuArg	conservative_inframe_insertion	Exon 2 of 2		NP_001139478.1
IGFALS	NR_027389.1 link	n.637_645dupAGCCTGCGC		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IGFALS	ENST00000215539.4 link	c.583_591dupAGCCTGCGC	p.Arg197_Glu198insSerLeuArg	conservative_inframe_insertion	Exon 2 of 2	1	NM_004970.3	ENSP00000215539.3
IGFALS	ENST00000415638.3 link	c.697_705dupAGCCTGCGC	p.Arg235_Glu236insSerLeuArg	conservative_inframe_insertion	Exon 2 of 2	2		ENSP00000416683.3
IGFALS	ENST00000568221.1 link	c.219_227dupAGCCTGCGC		3_prime_UTR_variant	Exon 2 of 2	4		ENSP00000456923.1
SPSB3	ENST00000569769.1 link	c.-13+1802_-13+1810dupAGCCTGCGC		intron_variant	Intron 1 of 4	3		ENSP00000455098.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

146626

AF XY:

0.0000252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000121

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1397100

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

689768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31760

American (AMR)

AF:

0.00

AC:

AN:

36260

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25160

East Asian (EAS)

AF:

0.00

AC:

AN:

35940

South Asian (SAS)

AF:

0.00

AC:

AN:

79816

European-Finnish (FIN)

AF:

0.0000458

AC:

AN:

43698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.0000352

AC:

AN:

1080792

Other (OTH)

AF:

0.000103

AC:

AN:

58022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000960

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Short stature due to primary acid-labile subunit deficiency

Pathogenic:1

Nov 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.9

Mutation Taster

=80/20

disease causing (ClinVar)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over