chr1-18876432-T-C

Variant names:

• chr1-18876432-T-C
• rs2230706
• NM_003748.4:c.1221A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003748.4(ALDH4A1):​c.1221A>G​(p.Ala407Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,606,196 control chromosomes in the GnomAD database, including 389,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31953 hom., cov: 32)
  • Exomes 𝑓: 0.70 (357845 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.128
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-18876432-T-C is Benign according to our data. Variant chr1-18876432-T-C is described in ClinVar as Benign. ClinVar VariationId is 294376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.128 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

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.1221A>G	p.Ala407Ala	synonymous	Exon 12 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1221A>G	p.Ala407Ala	synonymous	Exon 12 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001161504.2		c.1041A>G	p.Ala347Ala	synonymous	Exon 12 of 15	NP_001154976.1	P30038-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1221A>G	p.Ala407Ala	synonymous	Exon 12 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1221A>G	p.Ala407Ala	synonymous	Exon 12 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1185+776A>G		intron	N/A	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97277 AN: 151480 Hom.: 31934 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.677

GnomAD2 exomes AF: 0.698 AC: 167755 AN: 240402 AF XY: 0.700

Gnomad AFR exome AF: 0.483

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.710

Gnomad FIN exome AF: 0.649

Gnomad NFE exome AF: 0.693

Gnomad OTH exome AF: 0.709

GnomAD4 exome AF: 0.700 AC: 1018100 AN: 1454598 Hom.: 357845 Cov.: 56 AF XY: 0.701 AC XY: 507140 AN XY: 723398

African (AFR) AF: 0.474 AC: 15784 AN: 33332

American (AMR) AF: 0.795 AC: 35090 AN: 44116

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 18043 AN: 26058

East Asian (EAS) AF: 0.727 AC: 28719 AN: 39488

South Asian (SAS) AF: 0.737 AC: 63306 AN: 85850

European-Finnish (FIN) AF: 0.653 AC: 33302 AN: 50982

Middle Eastern (MID) AF: 0.679 AC: 3776 AN: 5562

European-Non Finnish (NFE) AF: 0.702 AC: 779026 AN: 1109156

Other (OTH) AF: 0.684 AC: 41054 AN: 60054

GnomAD4 genome AF: 0.642 AC: 97351 AN: 151598 Hom.: 31953 Cov.: 32 AF XY: 0.645 AC XY: 47792 AN XY: 74048

African (AFR) AF: 0.485 AC: 20061 AN: 41326

American (AMR) AF: 0.751 AC: 11467 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2352 AN: 3460

East Asian (EAS) AF: 0.720 AC: 3687 AN: 5120

South Asian (SAS) AF: 0.747 AC: 3586 AN: 4802

European-Finnish (FIN) AF: 0.650 AC: 6823 AN: 10494

Middle Eastern (MID) AF: 0.658 AC: 187 AN: 284

European-Non Finnish (NFE) AF: 0.694 AC: 47046 AN: 67826

Other (OTH) AF: 0.678 AC: 1427 AN: 2106

Alfa AF: 0.671 Hom.: 41283

Bravo AF: 0.644

Asia WGS AF: 0.706 AC: 2458 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hyperprolinemia type 2 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.62
DANN	Benign	0.68
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2230706; hg19: chr1-19202926; COSMIC: COSV51893163;