1-18871606-C-G

Variant names:

• chr1-18871606-C-G
• rs1138328
• NM_003748.4:c.*1239G>C

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.*1239G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,310 control chromosomes in the GnomAD database, including 4,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4487 hom., cov: 33)
  • Exomes 𝑓: 0.25 (5 hom.)
• Consequence: ALDH4A1 NM_003748.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.122
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-18871606-C-G is Benign according to our data. Variant chr1-18871606-C-G is described in ClinVar as Benign. ClinVar VariationId is 294334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.27 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.*1239G>C		3_prime_UTR	Exon 15 of 15	NP_003739.2
	ALDH4A1	NM_170726.3		c.*226G>C		3_prime_UTR	Exon 16 of 16	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.*1239G>C		3_prime_UTR	Exon 14 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.*1239G>C		3_prime_UTR	Exon 15 of 15	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.*226G>C		3_prime_UTR	Exon 16 of 16	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.*1239G>C		3_prime_UTR	Exon 14 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35720 AN: 152060 Hom.: 4485 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.250 AC: 33 AN: 132 Hom.: 5 Cov.: 0 AF XY: 0.213 AC XY: 23 AN XY: 108

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.200 AC: 2 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.286 AC: 28 AN: 98

Other (OTH) AF: 0.214 AC: 3 AN: 14

GnomAD4 genome AF: 0.235 AC: 35729 AN: 152178 Hom.: 4487 Cov.: 33 AF XY: 0.228 AC XY: 16963 AN XY: 74396

African (AFR) AF: 0.209 AC: 8657 AN: 41514

American (AMR) AF: 0.229 AC: 3500 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 967 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5174

South Asian (SAS) AF: 0.127 AC: 613 AN: 4830

European-Finnish (FIN) AF: 0.237 AC: 2505 AN: 10590

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18550 AN: 67992

Other (OTH) AF: 0.241 AC: 510 AN: 2114

Alfa AF: 0.243 Hom.: 589

Bravo AF: 0.237

Asia WGS AF: 0.0730 AC: 259 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyperprolinemia type 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.8
DANN	Benign	0.42
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	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: rs1138328; hg19: chr1-19198100; COSMIC: COSV51895732; COSMIC: COSV51895732;