rs41273175

Variant names:

• chr1-18877231-A-C
• rs41273175
• NM_003748.4:c.1162T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-18877231-A-C
• chr1-18877231-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003748.4(ALDH4A1):​c.1162T>G​(p.Phe388Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,456,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. F388L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.43
• Publications: 13 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1162T>G	p.Phe388Val	missense_variant	Exon 11 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1162T>G	p.Phe388Val	missense_variant	Exon 11 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1162T>G	p.Phe388Val	missense_variant	Exon 11 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.982T>G	p.Phe328Val	missense_variant	Exon 11 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1162T>G	p.Phe388Val	missense_variant	Exon 11 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1162T>G	p.Phe388Val	missense_variant	Exon 11 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1162T>G	p.Phe388Val	missense_variant	Exon 11 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.982T>G	p.Phe328Val	missense_variant	Exon 11 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1456126 Hom.: 0 Cov.: 33 AF XY: 0.00000967 AC XY: 7 AN XY: 723714

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.00 AC: 0 AN: 85032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52928

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

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1109250

Other (OTH) AF: 0.0000332 AC: 2 AN: 60154

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 105

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.066	T;.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.17	N;N;N;.
PhyloP100		4.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.89	N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0090	B;.;B;.
Vest4		0.81
MutPred		0.48		Gain of MoRF binding (P = 0.1152);Gain of MoRF binding (P = 0.1152);Gain of MoRF binding (P = 0.1152);.;
MVP		0.61
MPC		0.14
ClinPred		0.45	T
GERP RS		3.1
Varity_R		0.20
gMVP		0.86
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41273175; hg19: chr1-19203725;