NM_002860.4:c.809-330G>A

Variant names:

• chr10-95628822-C-T
• rs10882644
• NM_002860.4:c.809-330G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002860.4(ALDH18A1):​c.809-330G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 361,078 control chromosomes in the GnomAD database, including 17,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6712 hom., cov: 32)
  • Exomes 𝑓: 0.31 (10735 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.362
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-95628822-C-T is Benign according to our data. Variant chr10-95628822-C-T is described in ClinVar as Benign. ClinVar VariationId is 683818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4	c.809-330G>A		intron_variant	Intron 7 of 17	ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.809-330G>A		intron_variant	Intron 7 of 17	1	NM_002860.4	ENSP00000360268.2
ALDH18A1	ENST00000371221.3	c.803-330G>A		intron_variant	Intron 7 of 17	1		ENSP00000360265.3
ALDH18A1	ENST00000489386.1	n.32G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41626 AN: 151996 Hom.: 6720 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0440

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.255

GnomAD4 exome AF: 0.305 AC: 63743 AN: 208964 Hom.: 10735 Cov.: 0 AF XY: 0.294 AC XY: 33255 AN XY: 113276

African (AFR) AF: 0.131 AC: 797 AN: 6098

American (AMR) AF: 0.424 AC: 4218 AN: 9942

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 1214 AN: 5338

East Asian (EAS) AF: 0.0448 AC: 435 AN: 9712

South Asian (SAS) AF: 0.225 AC: 8256 AN: 36754

European-Finnish (FIN) AF: 0.310 AC: 2938 AN: 9476

Middle Eastern (MID) AF: 0.252 AC: 195 AN: 774

European-Non Finnish (NFE) AF: 0.352 AC: 42308 AN: 120118

Other (OTH) AF: 0.315 AC: 3382 AN: 10752

GnomAD4 genome AF: 0.274 AC: 41608 AN: 152114 Hom.: 6712 Cov.: 32 AF XY: 0.272 AC XY: 20224 AN XY: 74344

African (AFR) AF: 0.129 AC: 5353 AN: 41510

American (AMR) AF: 0.391 AC: 5975 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3466

East Asian (EAS) AF: 0.0435 AC: 226 AN: 5190

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4818

European-Finnish (FIN) AF: 0.317 AC: 3346 AN: 10560

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

European-Non Finnish (NFE) AF: 0.353 AC: 23981 AN: 67980

Other (OTH) AF: 0.252 AC: 533 AN: 2114

Alfa AF: 0.302 Hom.: 979

Bravo AF: 0.276

Asia WGS AF: 0.127 AC: 445 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.8
DANN	Benign	0.37
PhyloP100		-0.36
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: rs10882644; hg19: chr10-97388579;