rs28441017

Variant names:

• chr1-18879840-G-A
• rs28441017
• NM_003748.4:c.867-467C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003748.4(ALDH4A1):​c.867-467C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 152,092 control chromosomes in the GnomAD database, including 5,093 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5093 hom., cov: 33)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.50
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.867-467C>T		intron_variant	Intron 8 of 14	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.867-467C>T		intron_variant	Intron 8 of 15		NP_733844.1
ALDH4A1	NM_001319218.2	c.867-467C>T		intron_variant	Intron 8 of 13		NP_001306147.1
ALDH4A1	NM_001161504.2	c.687-467C>T		intron_variant	Intron 8 of 14		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.867-467C>T		intron_variant	Intron 8 of 14	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.867-467C>T		intron_variant	Intron 8 of 15	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.867-467C>T		intron_variant	Intron 8 of 13	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.687-467C>T		intron_variant	Intron 8 of 14	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37487 AN: 151974 Hom.: 5080 Cov.: 33

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.204

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.247 AC: 37543 AN: 152092 Hom.: 5093 Cov.: 33 AF XY: 0.253 AC XY: 18830 AN XY: 74358

African (AFR) AF: 0.302 AC: 12530 AN: 41486

American (AMR) AF: 0.293 AC: 4476 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3468

East Asian (EAS) AF: 0.203 AC: 1049 AN: 5162

South Asian (SAS) AF: 0.198 AC: 957 AN: 4826

European-Finnish (FIN) AF: 0.346 AC: 3661 AN: 10596

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13977 AN: 67936

Other (OTH) AF: 0.202 AC: 428 AN: 2114

Alfa AF: 0.224 Hom.: 6352

Bravo AF: 0.242

Asia WGS AF: 0.211 AC: 733 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.041
DANN	Benign	0.56
PhyloP100		-2.5
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: rs28441017; hg19: chr1-19206334;