rs10882640

Variant names:

• chr10-95610182-C-T
• rs10882640
• NM_002860.4:c.2206+15G>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.2206+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,192 control chromosomes in the GnomAD database, including 174,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12959 hom., cov: 31)
  • Exomes 𝑓: 0.46 (161480 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.231
• Publications: 10 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):

• ALDH18A1-related de Barsy syndrome

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• cutis laxa, autosomal dominant 3

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• P5CS deficiency

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

  Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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=-0.81).
• BP6: Variant 10-95610182-C-T is Benign according to our data. Variant chr10-95610182-C-T is described in ClinVar as Benign. ClinVar VariationId is 258825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002860.4. 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
	ALDH18A1	NM_002860.4	MANE Select	c.2206+15G>A		intron	N/A	NP_002851.2
	ALDH18A1	NM_001323413.2		c.2206+15G>A		intron	N/A	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.2206+15G>A		intron	N/A	NP_001310343.1	P54886-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH18A1	ENST00000371224.7	TSL:1 MANE Select	c.2206+15G>A		intron	N/A	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.2200+15G>A		intron	N/A	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.2206+15G>A		intron	N/A	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58801 AN: 151956 Hom.: 12971 Cov.: 31

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.0844

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.392

GnomAD2 exomes AF: 0.419 AC: 105115 AN: 250954 AF XY: 0.416

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.428

Gnomad EAS exome AF: 0.0855

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.461 AC: 672796 AN: 1460118 Hom.: 161480 Cov.: 33 AF XY: 0.456 AC XY: 331467 AN XY: 726422

African (AFR) AF: 0.187 AC: 6269 AN: 33450

American (AMR) AF: 0.534 AC: 23840 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 10929 AN: 26114

East Asian (EAS) AF: 0.0872 AC: 3457 AN: 39646

South Asian (SAS) AF: 0.310 AC: 26746 AN: 86212

European-Finnish (FIN) AF: 0.477 AC: 25442 AN: 53324

Middle Eastern (MID) AF: 0.409 AC: 2351 AN: 5750

European-Non Finnish (NFE) AF: 0.493 AC: 547545 AN: 1110616

Other (OTH) AF: 0.435 AC: 26217 AN: 60328

GnomAD4 genome AF: 0.387 AC: 58780 AN: 152074 Hom.: 12959 Cov.: 31 AF XY: 0.385 AC XY: 28588 AN XY: 74332

African (AFR) AF: 0.200 AC: 8320 AN: 41498

American (AMR) AF: 0.498 AC: 7597 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1481 AN: 3472

East Asian (EAS) AF: 0.0842 AC: 436 AN: 5176

South Asian (SAS) AF: 0.290 AC: 1396 AN: 4814

European-Finnish (FIN) AF: 0.472 AC: 4993 AN: 10578

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33205 AN: 67952

Other (OTH) AF: 0.388 AC: 819 AN: 2112

Alfa AF: 0.456 Hom.: 16721

Bravo AF: 0.385

Asia WGS AF: 0.173 AC: 607 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	ALDH18A1-related de Barsy syndrome (4)
-	-	3	not specified (3)
-	-	1	Autosomal recessive complex spastic paraplegia type 9B (1)
-	-	1	Cutis laxa, autosomal dominant 3 (1)
-	-	1	de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 (1)
-	-	1	Hereditary spastic paraplegia 9A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.5
DANN	Benign	0.53
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10882640;

hg19: chr10-97369939;

COSMIC: COSV64662210;

COSMIC: COSV64662210;