chr10-95637587-T-C

Variant names:

• chr10-95637587-T-C
• rs11188411
• NM_002860.4:c.304-151A>G

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.304-151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 877,912 control chromosomes in the GnomAD database, including 43,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6787 hom., cov: 32)
  • Exomes 𝑓: 0.30 (36440 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.12
• Publications: 6 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=-0.91).
• BP6: Variant 10-95637587-T-C is Benign according to our data. Variant chr10-95637587-T-C is described in ClinVar as Benign. ClinVar VariationId is 1297419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.387 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.304-151A>G		intron	N/A	NP_002851.2
	ALDH18A1	NM_001323413.2		c.304-151A>G		intron	N/A	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.304-151A>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.304-151A>G		intron	N/A	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.304-151A>G		intron	N/A	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.304-151A>G		intron	N/A	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42087 AN: 152010 Hom.: 6795 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.298 AC: 215932 AN: 725784 Hom.: 36440 AF XY: 0.295 AC XY: 110081 AN XY: 373418

African (AFR) AF: 0.121 AC: 2314 AN: 19104

American (AMR) AF: 0.433 AC: 11503 AN: 26536

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 3838 AN: 17942

East Asian (EAS) AF: 0.0491 AC: 1602 AN: 32636

South Asian (SAS) AF: 0.220 AC: 12718 AN: 57822

European-Finnish (FIN) AF: 0.313 AC: 10244 AN: 32740

Middle Eastern (MID) AF: 0.226 AC: 633 AN: 2804

European-Non Finnish (NFE) AF: 0.325 AC: 162908 AN: 500760

Other (OTH) AF: 0.287 AC: 10172 AN: 35440

GnomAD4 genome AF: 0.277 AC: 42069 AN: 152128 Hom.: 6787 Cov.: 32 AF XY: 0.275 AC XY: 20446 AN XY: 74368

African (AFR) AF: 0.138 AC: 5731 AN: 41490

American (AMR) AF: 0.395 AC: 6043 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3472

East Asian (EAS) AF: 0.0435 AC: 225 AN: 5176

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4818

European-Finnish (FIN) AF: 0.316 AC: 3348 AN: 10592

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23983 AN: 67976

Other (OTH) AF: 0.256 AC: 542 AN: 2114

Alfa AF: 0.269 Hom.: 2525

Bravo AF: 0.280

Asia WGS AF: 0.128 AC: 447 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.31
DANN	Benign	0.70
PhyloP100		-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

Other links and lift over

dbSNP: rs11188411; hg19: chr10-97397344;