chr1-18885513-G-A

Variant names:

• chr1-18885513-G-A
• rs139640415
• NM_003748.4:c.413C>T
• ALDH4A1 p.Pro138Leu

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003748.4(ALDH4A1):​c.413C>T​(p.Pro138Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,542,014 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P138P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 6.21
• Publications: 5 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009564936).
• BP6: Variant 1-18885513-G-A is Benign according to our data. Variant chr1-18885513-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294391.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00237 (347/146580) while in subpopulation AFR AF = 0.004 (160/40034). AF 95% confidence interval is 0.00349. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.413C>T	p.Pro138Leu	missense	Exon 5 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.413C>T	p.Pro138Leu	missense	Exon 5 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.413C>T	p.Pro138Leu	missense	Exon 5 of 14	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.413C>T	p.Pro138Leu	missense	Exon 5 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.413C>T	p.Pro138Leu	missense	Exon 5 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.413C>T	p.Pro138Leu	missense	Exon 5 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 347 AN: 146464 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000415

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000228

Gnomad FIN AF: 0.000624

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00258

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.00128 AC: 286 AN: 223664 AF XY: 0.00119

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.000217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000913

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00241 AC: 3359 AN: 1395434 Hom.: 4 Cov.: 37 AF XY: 0.00236 AC XY: 1637 AN XY: 692414

African (AFR) AF: 0.00285 AC: 90 AN: 31596

American (AMR) AF: 0.000293 AC: 12 AN: 41002

Ashkenazi Jewish (ASJ) AF: 0.0000418 AC: 1 AN: 23902

East Asian (EAS) AF: 0.00 AC: 0 AN: 35018

South Asian (SAS) AF: 0.0000360 AC: 3 AN: 83380

European-Finnish (FIN) AF: 0.00156 AC: 75 AN: 47940

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5460

European-Non Finnish (NFE) AF: 0.00290 AC: 3105 AN: 1070962

Other (OTH) AF: 0.00128 AC: 72 AN: 56174

GnomAD4 genome AF: 0.00237 AC: 347 AN: 146580 Hom.: 1 Cov.: 31 AF XY: 0.00212 AC XY: 151 AN XY: 71220

African (AFR) AF: 0.00400 AC: 160 AN: 40034

American (AMR) AF: 0.000415 AC: 6 AN: 14466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 4664

South Asian (SAS) AF: 0.000228 AC: 1 AN: 4390

European-Finnish (FIN) AF: 0.000624 AC: 6 AN: 9614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00256 AC: 171 AN: 66752

Other (OTH) AF: 0.00146 AC: 3 AN: 2056

Alfa AF: 0.00214 Hom.: 3

Bravo AF: 0.00223

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hyperprolinemia type 2 (2)
-	-	1	ALDH4A1-related disorder (1)
-	1	-	Intellectual disability (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.2
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.57
Mutation Taster		=83/17	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs139640415; hg19: chr1-19212007; COSMIC: COSV99311564; COSMIC: COSV99311564;