rs2275273

Variant names:

• chr10-95637470-T-C
• rs2275273
• NM_002860.4:c.304-34A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-95637470-T-C
• chr10-95637470-T-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.304-34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,611,086 control chromosomes in the GnomAD database, including 397,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.66 (33725 hom., cov: 30)
  • Exomes 𝑓: 0.70 (363677 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00700
• Publications: 13 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):

• autosomal recessive complex spastic paraplegia type 9B

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

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp, Orphanet
• 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-95637470-T-C is Benign according to our data. Variant chr10-95637470-T-C is described in ClinVar as Benign. ClinVar VariationId is 258826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 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.304-34A>G		intron	N/A	NP_002851.2
	ALDH18A1	NM_001323413.2		c.304-34A>G		intron	N/A	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.304-34A>G		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.304-34A>G		intron	N/A	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.304-34A>G		intron	N/A	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.304-34A>G		intron	N/A	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100605 AN: 151806 Hom.: 33718 Cov.: 30

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.688 AC: 170300 AN: 247366 AF XY: 0.687

Gnomad AFR exome AF: 0.561

Gnomad AMR exome AF: 0.699

Gnomad ASJ exome AF: 0.689

Gnomad EAS exome AF: 0.764

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.716

Gnomad OTH exome AF: 0.688

GnomAD4 exome AF: 0.705 AC: 1028309 AN: 1459160 Hom.: 363677 Cov.: 40 AF XY: 0.702 AC XY: 509859 AN XY: 725900

African (AFR) AF: 0.551 AC: 18440 AN: 33438

American (AMR) AF: 0.700 AC: 31211 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 18227 AN: 26124

East Asian (EAS) AF: 0.705 AC: 27963 AN: 39682

South Asian (SAS) AF: 0.625 AC: 53858 AN: 86166

European-Finnish (FIN) AF: 0.653 AC: 34094 AN: 52192

Middle Eastern (MID) AF: 0.675 AC: 3878 AN: 5748

European-Non Finnish (NFE) AF: 0.719 AC: 798438 AN: 1110866

Other (OTH) AF: 0.699 AC: 42200 AN: 60332

GnomAD4 genome AF: 0.663 AC: 100656 AN: 151926 Hom.: 33725 Cov.: 30 AF XY: 0.659 AC XY: 48966 AN XY: 74264

African (AFR) AF: 0.563 AC: 23314 AN: 41384

American (AMR) AF: 0.689 AC: 10513 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2367 AN: 3468

East Asian (EAS) AF: 0.742 AC: 3818 AN: 5148

South Asian (SAS) AF: 0.606 AC: 2912 AN: 4808

European-Finnish (FIN) AF: 0.639 AC: 6755 AN: 10566

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.717 AC: 48735 AN: 67976

Other (OTH) AF: 0.656 AC: 1385 AN: 2112

Alfa AF: 0.694 Hom.: 105219

Bravo AF: 0.665

Asia WGS AF: 0.663 AC: 2307 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ALDH18A1-related de Barsy syndrome (1)
-	-	1	Autosomal recessive complex spastic paraplegia type 9B (1)
-	-	1	Cutis laxa, autosomal dominant 3 (1)
-	-	1	Hereditary spastic paraplegia 9A (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.6
DANN	Benign	0.55
PhyloP100		-0.0070
BranchPoint Hunter		2.0
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: rs2275273; hg19: chr10-97397227;