rs1804934

Variant names:

• chr10-95611389-G-A
• rs1804934
• NM_002860.4:c.1977C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002860.4(ALDH18A1):​c.1977C>T​(p.Ser659Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,614,154 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (76 hom., cov: 33)
  • Exomes 𝑓: 0.025 (474 hom.)
• Consequence: ALDH18A1 NM_002860.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.90
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-95611389-G-A is Benign according to our data. Variant chr10-95611389-G-A is described in ClinVar as Benign. ClinVar VariationId is 301761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0289 (4398/152266) while in subpopulation AFR AF = 0.0402 (1670/41540). AF 95% confidence interval is 0.0386. There are 76 homozygotes in GnomAd4. There are 2090 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 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.1977C>T	p.Ser659Ser	synonymous	Exon 16 of 18	NP_002851.2
	ALDH18A1	NM_001323413.2		c.1977C>T	p.Ser659Ser	synonymous	Exon 16 of 18	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.1977C>T	p.Ser659Ser	synonymous	Exon 16 of 18	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.1977C>T	p.Ser659Ser	synonymous	Exon 16 of 18	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.1971C>T	p.Ser657Ser	synonymous	Exon 16 of 18	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.1977C>T	p.Ser659Ser	synonymous	Exon 16 of 18	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4394 AN: 152148 Hom.: 76 Cov.: 33

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0319

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0231 AC: 5808 AN: 251446 AF XY: 0.0226

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0443

Gnomad EAS exome AF: 0.0117

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0248 AC: 36307 AN: 1461888 Hom.: 474 Cov.: 34 AF XY: 0.0243 AC XY: 17702 AN XY: 727244

African (AFR) AF: 0.0428 AC: 1432 AN: 33480

American (AMR) AF: 0.0213 AC: 951 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 1191 AN: 26136

East Asian (EAS) AF: 0.0139 AC: 553 AN: 39700

South Asian (SAS) AF: 0.0164 AC: 1412 AN: 86258

European-Finnish (FIN) AF: 0.0177 AC: 947 AN: 53418

Middle Eastern (MID) AF: 0.0298 AC: 172 AN: 5768

European-Non Finnish (NFE) AF: 0.0251 AC: 27865 AN: 1112008

Other (OTH) AF: 0.0295 AC: 1784 AN: 60396

GnomAD4 genome AF: 0.0289 AC: 4398 AN: 152266 Hom.: 76 Cov.: 33 AF XY: 0.0281 AC XY: 2090 AN XY: 74456

African (AFR) AF: 0.0402 AC: 1670 AN: 41540

American (AMR) AF: 0.0318 AC: 487 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 156 AN: 3470

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5188

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4830

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10600

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0246 AC: 1671 AN: 68026

Other (OTH) AF: 0.0369 AC: 78 AN: 2112

Alfa AF: 0.0266 Hom.: 109

Bravo AF: 0.0311

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0291

EpiControl AF: 0.0267

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.44
DANN	Benign	0.60
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1804934; hg19: chr10-97371146; COSMIC: COSV64662726;