1-18874494-G-C

Position:

• chr1-18874494-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003748.4(ALDH4A1):​c.1548C>G​(p.Gly516Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G516G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1548C>G	p.Gly516Gly	synonymous_variant	14/15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1548C>G	p.Gly516Gly	synonymous_variant	14/16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1395C>G	p.Gly465Gly	synonymous_variant	13/14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1368C>G	p.Gly456Gly	synonymous_variant	14/15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1548C>G	p.Gly516Gly	synonymous_variant	14/15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1548C>G	p.Gly516Gly	synonymous_variant	14/16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1395C>G	p.Gly465Gly	synonymous_variant	13/14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1368C>G	p.Gly456Gly	synonymous_variant	14/15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749348; hg19: chr1-19200988;