16-1791590-GT-AC

Variant names:

• chr16-1791590-GT-AC
• NM_004970.3:c.827_828delACinsGT
• IGFALS p.Asn276Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Very_Strong

The NM_004970.3(IGFALS):​c.827_828delACinsGT​(p.Asn276Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGFALS NM_004970.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.14
• 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_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_004970.3 (IGFALS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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.827_828delACinsGT	p.Asn276Ser	missense	N/A	NP_004961.1	P35858-1
	IGFALS	NM_001146006.2		c.941_942delACinsGT	p.Asn314Ser	missense	N/A	NP_001139478.1	P35858-2
	IGFALS	NR_027389.1		n.881_882delACinsGT		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.827_828delACinsGT	p.Asn276Ser	missense	N/A	ENSP00000215539.3	P35858-1
	IGFALS	ENST00000415638.3	TSL:2	c.941_942delACinsGT	p.Asn314Ser	missense	N/A	ENSP00000416683.3	P35858-2
	IGFALS	ENST00000897144.1		c.902_903delACinsGT	p.Asn301Ser	missense	N/A	ENSP00000567203.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-1841591;