NM_003748.4:c.940+122A>C

Variant names:

• chr1-18879178-T-G
• rs28497538
• NM_003748.4:c.940+122A>C

Variant summary

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

The NM_003748.4(ALDH4A1):​c.940+122A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 947,762 control chromosomes in the GnomAD database, including 76,105 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 0.43 (14332 hom., cov: 32)
  • Exomes 𝑓: 0.39 (61773 hom.)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.63
• 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: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 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.940+122A>C		intron	N/A	NP_003739.2
	ALDH4A1	NM_170726.3		c.940+122A>C		intron	N/A	NP_733844.1	P30038-1
	ALDH4A1	NM_001319218.2		c.940+122A>C		intron	N/A	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.940+122A>C		intron	N/A	ENSP00000364490.3	P30038-1
	ALDH4A1	ENST00000290597.9	TSL:1	c.940+122A>C		intron	N/A	ENSP00000290597.5	P30038-1
	ALDH4A1	ENST00000538839.5	TSL:1	c.940+122A>C		intron	N/A	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64876 AN: 151922 Hom.: 14310 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.389 AC: 309280 AN: 795722 Hom.: 61773 AF XY: 0.387 AC XY: 157781 AN XY: 407868

African (AFR) AF: 0.495 AC: 9959 AN: 20136

American (AMR) AF: 0.462 AC: 15405 AN: 33322

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 4696 AN: 19300

East Asian (EAS) AF: 0.310 AC: 10132 AN: 32708

South Asian (SAS) AF: 0.403 AC: 25024 AN: 62104

European-Finnish (FIN) AF: 0.508 AC: 23627 AN: 46550

Middle Eastern (MID) AF: 0.295 AC: 1301 AN: 4404

European-Non Finnish (NFE) AF: 0.379 AC: 204673 AN: 539338

Other (OTH) AF: 0.382 AC: 14463 AN: 37860

GnomAD4 genome AF: 0.427 AC: 64944 AN: 152040 Hom.: 14332 Cov.: 32 AF XY: 0.435 AC XY: 32302 AN XY: 74318

African (AFR) AF: 0.489 AC: 20259 AN: 41454

American (AMR) AF: 0.467 AC: 7147 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 826 AN: 3466

East Asian (EAS) AF: 0.364 AC: 1878 AN: 5154

South Asian (SAS) AF: 0.424 AC: 2043 AN: 4818

European-Finnish (FIN) AF: 0.515 AC: 5447 AN: 10574

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

European-Non Finnish (NFE) AF: 0.384 AC: 26073 AN: 67962

Other (OTH) AF: 0.414 AC: 876 AN: 2114

Alfa AF: 0.392 Hom.: 17534

Bravo AF: 0.420

Asia WGS AF: 0.410 AC: 1427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.80
PhyloP100		-3.6
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: rs28497538; hg19: chr1-19205672;