rs147471420

Variant names:

• chr1-18877455-C-T
• rs147471420
• NM_003748.4:c.1098G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_003748.4(ALDH4A1):​c.1098G>A​(p.Gly366Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,593,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.27
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 1-18877455-C-T is Benign according to our data. Variant chr1-18877455-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294378.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00044 (67/152372) while in subpopulation AMR AF = 0.000914 (14/15310). AF 95% confidence interval is 0.000552. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1098G>A	p.Gly366Gly	synonymous	Exon 10 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.1098G>A	p.Gly366Gly	synonymous	Exon 10 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.1098G>A	p.Gly366Gly	synonymous	Exon 10 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.1098G>A	p.Gly366Gly	synonymous	Exon 10 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.1098G>A	p.Gly366Gly	synonymous	Exon 10 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.1098G>A	p.Gly366Gly	synonymous	Exon 10 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000625 AC: 136 AN: 217748 AF XY: 0.000569

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000790

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.000873

Gnomad OTH exome AF: 0.000911

GnomAD4 exome AF: 0.000551 AC: 794 AN: 1441166 Hom.: 1 Cov.: 33 AF XY: 0.000515 AC XY: 368 AN XY: 714972

African (AFR) AF: 0.0000302 AC: 1 AN: 33156

American (AMR) AF: 0.000709 AC: 30 AN: 42328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 38862

South Asian (SAS) AF: 0.0000360 AC: 3 AN: 83328

European-Finnish (FIN) AF: 0.000965 AC: 49 AN: 50758

Middle Eastern (MID) AF: 0.000545 AC: 3 AN: 5506

European-Non Finnish (NFE) AF: 0.000611 AC: 673 AN: 1101958

Other (OTH) AF: 0.000587 AC: 35 AN: 59576

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152372 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74500

African (AFR) AF: 0.0000240 AC: 1 AN: 41592

American (AMR) AF: 0.000914 AC: 14 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000512 Hom.: 0

Bravo AF: 0.000521

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hyperprolinemia type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs147471420; hg19: chr1-19203949;