rs149309642

Variant names:

• chr10-95606946-G-A
• rs149309642
• NM_002860.4:c.2207-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002860.4(ALDH18A1):​c.2207-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,613,784 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (34 hom.)
• Consequence: ALDH18A1 NM_002860.4 splice_region, intron
• Scores: Splicing: ADA: 0.008707
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.80
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-95606946-G-A is Benign according to our data. Variant chr10-95606946-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 301756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00458 (697/152210) while in subpopulation AMR AF = 0.00733 (112/15284). AF 95% confidence interval is 0.00668. There are 6 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR,SD gene

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.2207-3C>T		splice_region intron	N/A	NP_002851.2
	ALDH18A1	NM_001323413.2		c.2207-3C>T		splice_region intron	N/A	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.2207-3C>T		splice_region 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.2207-3C>T		splice_region intron	N/A	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.2201-3C>T		splice_region intron	N/A	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.2207-3C>T		splice_region intron	N/A	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 700 AN: 152092 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00453 AC: 1137 AN: 250964 AF XY: 0.00444

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00716

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00620 AC: 9068 AN: 1461574 Hom.: 34 Cov.: 33 AF XY: 0.00620 AC XY: 4511 AN XY: 727114

African (AFR) AF: 0.00152 AC: 51 AN: 33468

American (AMR) AF: 0.00467 AC: 209 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00278 AC: 240 AN: 86242

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53404

Middle Eastern (MID) AF: 0.0181 AC: 103 AN: 5688

European-Non Finnish (NFE) AF: 0.00722 AC: 8025 AN: 1111848

Other (OTH) AF: 0.00576 AC: 348 AN: 60374

GnomAD4 genome AF: 0.00458 AC: 697 AN: 152210 Hom.: 6 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74422

African (AFR) AF: 0.00149 AC: 62 AN: 41512

American (AMR) AF: 0.00733 AC: 112 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00721 AC: 490 AN: 68008

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00561 Hom.: 5

Bravo AF: 0.00490

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00776

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	ALDH18A1-related de Barsy syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	ALDH18A1-related disorder (1)
-	-	1	de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 (1)
-	-	1	Hereditary spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		1.8
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0087
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.010		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: rs149309642; hg19: chr10-97366703;