rs6695033

Variant names:

• chr1-18875425-T-C
• rs6695033
• NM_003748.4:c.1417A>G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 4.54
• Publications: 16 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: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1417A>G	p.Thr473Ala	missense_variant	Exon 13 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1417A>G	p.Thr473Ala	missense_variant	Exon 13 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1264A>G	p.Thr422Ala	missense_variant	Exon 12 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1237A>G	p.Thr413Ala	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.1417A>G	p.Thr473Ala	missense_variant	Exon 13 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1417A>G	p.Thr473Ala	missense_variant	Exon 13 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1264A>G	p.Thr422Ala	missense_variant	Exon 12 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1237A>G	p.Thr413Ala	missense_variant	Exon 13 of 15	2		ENSP00000442988.1

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

GnomAD2 exomes AF: 0.0310 AC: 7787 AN: 251476 AF XY: 0.0287

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 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

African (AFR) AF: 0.166 AC: 5563 AN: 33476

American (AMR) AF: 0.0239 AC: 1067 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 831 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0172 AC: 1485 AN: 86258

European-Finnish (FIN) AF: 0.0268 AC: 1433 AN: 53414

Middle Eastern (MID) AF: 0.0668 AC: 385 AN: 5766

European-Non Finnish (NFE) AF: 0.0211 AC: 23420 AN: 1111996

Other (OTH) AF: 0.0330 AC: 1995 AN: 60394

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

African (AFR) AF: 0.161 AC: 6693 AN: 41502

American (AMR) AF: 0.0371 AC: 567 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 139 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0187 AC: 90 AN: 4822

European-Finnish (FIN) AF: 0.0235 AC: 249 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0224 AC: 1524 AN: 67988

Other (OTH) AF: 0.0521 AC: 110 AN: 2110

Alfa AF: 0.0342 Hom.: 927

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
LIST_S2	Pathogenic	0.98	.;D;D;D
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;M;.
PhyloP100		4.5
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
Mutation Taster		=29/71	polymorphism (auto)

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: rs6695033; hg19: chr1-19201919;