3-52199266-CCA-GCT

Variant names:

• chr3-52199266-CCA-GCT
• NM_000688.6:c.25_27delCCAinsGCT
• ALAS1 p.Pro9Ala

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000688.6(ALAS1):​c.25_27delCCAinsGCT​(p.Pro9Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALAS1 NM_000688.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

ALAS1 (HGNC:396): (5'-aminolevulinate synthase 1) This gene encodes the mitochondrial enzyme which is catalyzes the rate-limiting step in heme (iron-protoporphyrin) biosynthesis. The enzyme encoded by this gene is the housekeeping enzyme; a separate gene encodes a form of the enzyme that is specific for erythroid tissue. The level of the mature encoded protein is regulated by heme: high levels of heme down-regulate the mature enzyme in mitochondria while low heme levels up-regulate. A pseudogene of this gene is located on chromosome 12. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000688.6. 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
	ALAS1	NM_000688.6	MANE Select	c.25_27delCCAinsGCT	p.Pro9Ala	missense	N/A	NP_000679.1	P13196-1
	ALAS1	NM_001304444.1		c.76_78delCCAinsGCT	p.Pro26Ala	missense	N/A	NP_001291373.1	B4DVA0
	ALAS1	NM_001304443.1		c.25_27delCCAinsGCT	p.Pro9Ala	missense	N/A	NP_001291372.1	P13196-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALAS1	ENST00000484952.6	TSL:1 MANE Select	c.25_27delCCAinsGCT	p.Pro9Ala	missense	N/A	ENSP00000418779.1	P13196-1
	ALAS1	ENST00000310271.6	TSL:1	c.25_27delCCAinsGCT	p.Pro9Ala	missense	N/A	ENSP00000309259.2	P13196-1
	ALAS1	ENST00000469224.5	TSL:1	c.25_27delCCAinsGCT	p.Pro9Ala	missense	N/A	ENSP00000417719.1	P13196-1

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		7.6

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: chr3-52233282;