rs6695033

Positions:

• chr1-18875425-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):​c.1417A>G​(p.Thr473Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0282 in 1,614,048 control chromosomes in the GnomAD database, including 1,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (588 hom., cov: 33)
  • Exomes 𝑓: 0.025 (915 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.54

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016415417).
• BP6: Variant 1-18875425-T-C is Benign according to our data. Variant chr1-18875425-T-C is described in ClinVar as [Benign]. Clinvar id is 294366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875425-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.1417A>G	p.Thr473Ala	missense_variant	13/15	ENST00000375341.8
ALDH4A1	NM_170726.3	c.1417A>G	p.Thr473Ala	missense_variant	13/16
ALDH4A1	NM_001319218.2	c.1264A>G	p.Thr422Ala	missense_variant	12/14
ALDH4A1	NM_001161504.2	c.1237A>G	p.Thr413Ala	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1417A>G	p.Thr473Ala	missense_variant	13/15	1	NM_003748.4	P1
ALDH4A1	ENST00000290597.9	c.1417A>G	p.Thr473Ala	missense_variant	13/16	1		P1
ALDH4A1	ENST00000538839.5	c.1264A>G	p.Thr422Ala	missense_variant	12/14	1
ALDH4A1	ENST00000538309.5	c.1237A>G	p.Thr413Ala	missense_variant	13/15	2

Frequencies

GnomAD3 genomes AF: 0.0617 AC: 9375 AN: 152066 Hom.: 586 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0527

GnomAD3 exomes AF: 0.0310 AC: 7787 AN: 251476 Hom.: 316 AF XY: 0.0287 AC XY: 3906 AN XY: 135918

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0164

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0362

GnomAD4 exome AF: 0.0247 AC: 36180 AN: 1461864 Hom.: 915 Cov.: 31 AF XY: 0.0243 AC XY: 17647 AN XY: 727240

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.0318

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0211

Gnomad4 OTH exome AF: 0.0330

GnomAD4 genome AF: 0.0617 AC: 9392 AN: 152184 Hom.: 588 Cov.: 33 AF XY: 0.0595 AC XY: 4428 AN XY: 74414

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0371

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0187

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.0224

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0298 Hom.: 352

Bravo AF: 0.0676

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.156 AC: 687

ESP6500EA AF: 0.0223 AC: 192

ExAC AF: 0.0335 AC: 4071

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0278

EpiControl AF: 0.0272

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;T;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.60	D
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;M;.
MutationTaster	Benign	2.3e-8	P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;N;D;D
REVEL	Benign	0.15
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.068	T;T;T;T
Polyphen		0.34	B;.;B;.
Vest4		0.41
MPC		0.35
ClinPred		0.022	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.72

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: rs6695033; hg19: chr1-19201919;