NM_002860.4:c.1153-30T>C

Variant names:

• chr10-95625485-A-G
• rs10509688
• NM_002860.4:c.1153-30T>C

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.1153-30T>C variant causes a intron change. The variant allele was found at a frequency of 0.166 in 1,582,184 control chromosomes in the GnomAD database, including 24,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2023 hom., cov: 30)
  • Exomes 𝑓: 0.17 (22743 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.69
• Publications: 9 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: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-95625485-A-G is Benign according to our data. Variant chr10-95625485-A-G is described in ClinVar as Benign. ClinVar VariationId is 258824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 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.1153-30T>C		intron	N/A	NP_002851.2
	ALDH18A1	NM_001323413.2		c.1153-30T>C		intron	N/A	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.1153-30T>C		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.1153-30T>C		intron	N/A	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.1147-30T>C		intron	N/A	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.1153-30T>C		intron	N/A	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21845 AN: 151832 Hom.: 2011 Cov.: 30

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.175 AC: 43908 AN: 250610 AF XY: 0.176

Gnomad AFR exome AF: 0.0729

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.169 AC: 241273 AN: 1430234 Hom.: 22743 Cov.: 24 AF XY: 0.168 AC XY: 119967 AN XY: 713658

African (AFR) AF: 0.0666 AC: 2183 AN: 32760

American (AMR) AF: 0.114 AC: 5089 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3149 AN: 25916

East Asian (EAS) AF: 0.468 AC: 18501 AN: 39522

South Asian (SAS) AF: 0.161 AC: 13738 AN: 85580

European-Finnish (FIN) AF: 0.191 AC: 10088 AN: 52866

Middle Eastern (MID) AF: 0.103 AC: 586 AN: 5716

European-Non Finnish (NFE) AF: 0.164 AC: 178234 AN: 1083924

Other (OTH) AF: 0.164 AC: 9705 AN: 59288

GnomAD4 genome AF: 0.144 AC: 21888 AN: 151950 Hom.: 2023 Cov.: 30 AF XY: 0.144 AC XY: 10708 AN XY: 74258

African (AFR) AF: 0.0751 AC: 3114 AN: 41468

American (AMR) AF: 0.119 AC: 1818 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2482 AN: 5108

South Asian (SAS) AF: 0.156 AC: 752 AN: 4808

European-Finnish (FIN) AF: 0.179 AC: 1889 AN: 10576

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11002 AN: 67942

Other (OTH) AF: 0.134 AC: 281 AN: 2104

Alfa AF: 0.156 Hom.: 6049

Bravo AF: 0.139

Asia WGS AF: 0.323 AC: 1120 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.68
PhyloP100		4.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs10509688; hg19: chr10-97385242; COSMIC: COSV64662267;