rs4417206

Variant names:

• chr10-95636713-A-C
• rs4417206
• NM_002860.4:c.558+380T>G

Variant summary

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

The NM_002860.4(ALDH18A1):​c.558+380T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 152,172 control chromosomes in the GnomAD database, including 6,782 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 0.28 (6782 hom., cov: 33)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.173
• Publications: 2 publications found

Genes affected

ALDH18A1 (HGNC:9722): (aldehyde dehydrogenase 18 family member A1) This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]

ALDH18A1 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 3

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• ALDH18A1-related de Barsy syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive complex spastic paraplegia type 9B

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• P5CS deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• hereditary spastic paraplegia 9A

  Inheritance: AD, SD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• autosomal dominant complex spastic paraplegia type 9B

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4	c.558+380T>G		intron_variant	Intron 5 of 17	ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.558+380T>G		intron_variant	Intron 5 of 17	1	NM_002860.4	ENSP00000360268.2
ALDH18A1	ENST00000371221.3	c.558+380T>G		intron_variant	Intron 5 of 17	1		ENSP00000360265.3

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42091 AN: 152054 Hom.: 6790 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.276 AC: 42073 AN: 152172 Hom.: 6782 Cov.: 33 AF XY: 0.275 AC XY: 20447 AN XY: 74408

African (AFR) AF: 0.138 AC: 5729 AN: 41546

American (AMR) AF: 0.396 AC: 6044 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 756 AN: 3468

East Asian (EAS) AF: 0.0436 AC: 226 AN: 5182

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4826

European-Finnish (FIN) AF: 0.316 AC: 3349 AN: 10586

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23984 AN: 67972

Other (OTH) AF: 0.257 AC: 543 AN: 2114

Alfa AF: 0.303 Hom.: 993

Bravo AF: 0.280

Asia WGS AF: 0.128 AC: 448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Benign	0.91
PhyloP100		-0.17
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: rs4417206; hg19: chr10-97396470;