rs4912075

Variant names:

• chr1-18888924-T-C
• rs4912075
• NM_003748.4:c.249+438A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-18888924-T-C
• chr1-18888924-T-G

Variant summary

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

The NM_003748.4(ALDH4A1):​c.249+438A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.553 in 152,150 control chromosomes in the GnomAD database, including 25,795 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 0.55 (25795 hom., cov: 33)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.762
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	NM_003748.4	MANE Select	c.249+438A>G		intron	N/A	NP_003739.2
	ALDH4A1	NM_170726.3		c.249+438A>G		intron	N/A	NP_733844.1
	ALDH4A1	NM_001319218.2		c.249+438A>G		intron	N/A	NP_001306147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.249+438A>G		intron	N/A	ENSP00000364490.3
	ALDH4A1	ENST00000290597.9	TSL:1	c.249+438A>G		intron	N/A	ENSP00000290597.5
	ALDH4A1	ENST00000538839.5	TSL:1	c.249+438A>G		intron	N/A	ENSP00000446071.1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83972 AN: 152032 Hom.: 25742 Cov.: 33

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.522

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

GnomAD4 genome AF: 0.553 AC: 84079 AN: 152150 Hom.: 25795 Cov.: 33 AF XY: 0.553 AC XY: 41125 AN XY: 74366

African (AFR) AF: 0.839 AC: 34860 AN: 41540

American (AMR) AF: 0.478 AC: 7300 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1433 AN: 3472

East Asian (EAS) AF: 0.574 AC: 2963 AN: 5164

South Asian (SAS) AF: 0.489 AC: 2361 AN: 4826

European-Finnish (FIN) AF: 0.444 AC: 4694 AN: 10574

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28932 AN: 67968

Other (OTH) AF: 0.522 AC: 1105 AN: 2116

Alfa AF: 0.458 Hom.: 30406

Bravo AF: 0.569

Asia WGS AF: 0.542 AC: 1888 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.1
DANN	Benign	0.59
PhyloP100		-0.76
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: rs4912075; hg19: chr1-19215418;