1-18875462-A-T

Variant names:

• chr1-18875462-A-T
• rs2230708
• NM_003748.4:c.1380T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003748.4(ALDH4A1):​c.1380T>A​(p.Asp460Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D460G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 22 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089517534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1380T>A	p.Asp460Glu	missense_variant	Exon 13 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1380T>A	p.Asp460Glu	missense_variant	Exon 13 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1227T>A	p.Asp409Glu	missense_variant	Exon 12 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1200T>A	p.Asp400Glu	missense_variant	Exon 13 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1380T>A	p.Asp460Glu	missense_variant	Exon 13 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1380T>A	p.Asp460Glu	missense_variant	Exon 13 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1227T>A	p.Asp409Glu	missense_variant	Exon 12 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1200T>A	p.Asp400Glu	missense_variant	Exon 13 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 67 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 83439

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0030
DANN	Benign	0.91
DEOGEN2	Uncertain	0.43	T;.;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Uncertain	0.88	.;D;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.090	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N;.;N;.
PhyloP100		-1.3
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D;N;D;D
REVEL	Benign	0.085
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.10	B;.;B;.
Vest4		0.12
MutPred		0.56		Loss of ubiquitination at K464 (P = 0.1062);.;Loss of ubiquitination at K464 (P = 0.1062);.;
MVP		0.14
MPC		0.14
ClinPred		0.50	D
GERP RS		-10
Varity_R		0.33
gMVP		0.49
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs2230708; hg19: chr1-19201956;