1-18885513-GG-AA

Variant names:

• chr1-18885513-GG-AA
• NM_003748.4:c.412_413delCCinsTT
• ALDH4A1 p.Pro138Leu

Variant summary

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

The NM_003748.4(ALDH4A1):​c.412_413delCCinsTT​(p.Pro138Leu) 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 Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P138P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.21
• Publications: 0 publications found

Genes affected

ALDH4A1 (HGNC:406): (aldehyde dehydrogenase 4 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. Deficiency of this enzyme is associated with type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2009]

ALDH4A1 Gene-Disease associations (from GenCC):

• hyperprolinemia type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

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_003748.4. 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
	ALDH4A1	NM_003748.4	MANE Select	c.412_413delCCinsTT	p.Pro138Leu	missense	N/A	NP_003739.2
	ALDH4A1	NM_170726.3		c.412_413delCCinsTT	p.Pro138Leu	missense	N/A	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.412_413delCCinsTT	p.Pro138Leu	missense	N/A	NP_001306147.1	P30038-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.412_413delCCinsTT	p.Pro138Leu	missense	N/A	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.412_413delCCinsTT	p.Pro138Leu	missense	N/A	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.412_413delCCinsTT	p.Pro138Leu	missense	N/A	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

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: chr1-19212007;