1-18881699-C-G

Variant names:

• chr1-18881699-C-G
• rs78532707
• NM_003748.4:c.866+1G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003748.4(ALDH4A1):​c.866+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH4A1 NM_003748.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.866+1G>C		splice_donor_variant, intron_variant	Intron 8 of 14	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.866+1G>C		splice_donor_variant, intron_variant	Intron 8 of 15		NP_733844.1
ALDH4A1	NM_001319218.2	c.866+1G>C		splice_donor_variant, intron_variant	Intron 8 of 13		NP_001306147.1
ALDH4A1	NM_001161504.2	c.686+1G>C		splice_donor_variant, intron_variant	Intron 8 of 14		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.866+1G>C		splice_donor_variant, intron_variant	Intron 8 of 14	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.866+1G>C		splice_donor_variant, intron_variant	Intron 8 of 15	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.866+1G>C		splice_donor_variant, intron_variant	Intron 8 of 13	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.686+1G>C		splice_donor_variant, intron_variant	Intron 8 of 14	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251218 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs78532707; hg19: chr1-19208193;