1-18874401-C-T

Variant names:

• chr1-18874401-C-T
• rs35657817
• NM_003748.4:c.1579+62G>A

Variant summary

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

The NM_003748.4(ALDH4A1):​c.1579+62G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,465,828 control chromosomes in the GnomAD database, including 54,931 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 0.29 (6716 hom., cov: 33)
  • Exomes 𝑓: 0.26 (48215 hom.)
• Consequence: ALDH4A1 NM_003748.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• 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: 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1579+62G>A		intron_variant	Intron 14 of 14	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1579+62G>A		intron_variant	Intron 14 of 15		NP_733844.1
ALDH4A1	NM_001319218.2	c.1426+62G>A		intron_variant	Intron 13 of 13		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1399+62G>A		intron_variant	Intron 14 of 14		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1579+62G>A		intron_variant	Intron 14 of 14	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1579+62G>A		intron_variant	Intron 14 of 15	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1426+62G>A		intron_variant	Intron 13 of 13	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1399+62G>A		intron_variant	Intron 14 of 14	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43498 AN: 151972 Hom.: 6711 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.292

GnomAD4 exome AF: 0.263 AC: 344881 AN: 1313738 Hom.: 48215 AF XY: 0.258 AC XY: 170403 AN XY: 659264

African (AFR) AF: 0.373 AC: 11273 AN: 30230

American (AMR) AF: 0.233 AC: 10316 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 7106 AN: 25054

East Asian (EAS) AF: 0.000541 AC: 21 AN: 38824

South Asian (SAS) AF: 0.139 AC: 11577 AN: 83142

European-Finnish (FIN) AF: 0.264 AC: 12814 AN: 48588

Middle Eastern (MID) AF: 0.312 AC: 1719 AN: 5508

European-Non Finnish (NFE) AF: 0.281 AC: 275784 AN: 982634

Other (OTH) AF: 0.257 AC: 14271 AN: 55500

GnomAD4 genome AF: 0.286 AC: 43530 AN: 152090 Hom.: 6716 Cov.: 33 AF XY: 0.279 AC XY: 20776 AN XY: 74358

African (AFR) AF: 0.372 AC: 15415 AN: 41470

American (AMR) AF: 0.255 AC: 3897 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5172

South Asian (SAS) AF: 0.130 AC: 626 AN: 4822

European-Finnish (FIN) AF: 0.254 AC: 2691 AN: 10578

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18797 AN: 67974

Other (OTH) AF: 0.288 AC: 609 AN: 2116

Alfa AF: 0.268 Hom.: 745

Bravo AF: 0.294

Asia WGS AF: 0.0850 AC: 300 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.046
DANN	Benign	0.43
PhyloP100		-1.0
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: rs35657817; hg19: chr1-19200895;