10-95606607-C-T

Variant names:

• chr10-95606607-C-T
• rs1053905
• NM_002860.4:c.*155G>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.*155G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,579,346 control chromosomes in the GnomAD database, including 203,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15315 hom., cov: 32)
  • Exomes 𝑓: 0.50 (188414 hom.)
• Consequence: ALDH18A1 NM_002860.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0270
• Publications: 16 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):

• cutis laxa, autosomal dominant 3

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive complex spastic paraplegia type 9B

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• P5CS deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• hereditary spastic paraplegia 9A

  Inheritance: AD, SD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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=-0.85).
• BP6: Variant 10-95606607-C-T is Benign according to our data. Variant chr10-95606607-C-T is described in ClinVar as Benign. ClinVar VariationId is 301753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4	c.*155G>A		3_prime_UTR_variant	Exon 18 of 18	ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.*155G>A		3_prime_UTR_variant	Exon 18 of 18	1	NM_002860.4	ENSP00000360268.2
ALDH18A1	ENST00000371221.3	c.*155G>A		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000360265.3

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63902 AN: 151962 Hom.: 15331 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.0849

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.428

GnomAD4 exome AF: 0.503 AC: 718183 AN: 1427266 Hom.: 188414 Cov.: 40 AF XY: 0.498 AC XY: 352518 AN XY: 707796

African (AFR) AF: 0.201 AC: 6549 AN: 32598

American (AMR) AF: 0.553 AC: 23259 AN: 42080

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 11819 AN: 24886

East Asian (EAS) AF: 0.0876 AC: 3443 AN: 39306

South Asian (SAS) AF: 0.323 AC: 26535 AN: 82200

European-Finnish (FIN) AF: 0.519 AC: 22746 AN: 43820

Middle Eastern (MID) AF: 0.448 AC: 1808 AN: 4040

European-Non Finnish (NFE) AF: 0.540 AC: 594190 AN: 1099374

Other (OTH) AF: 0.472 AC: 27834 AN: 58962

GnomAD4 genome AF: 0.420 AC: 63876 AN: 152080 Hom.: 15315 Cov.: 32 AF XY: 0.418 AC XY: 31045 AN XY: 74338

African (AFR) AF: 0.215 AC: 8925 AN: 41494

American (AMR) AF: 0.525 AC: 8021 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1673 AN: 3470

East Asian (EAS) AF: 0.0847 AC: 439 AN: 5180

South Asian (SAS) AF: 0.300 AC: 1449 AN: 4822

European-Finnish (FIN) AF: 0.510 AC: 5374 AN: 10540

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36541 AN: 67980

Other (OTH) AF: 0.423 AC: 891 AN: 2106

Alfa AF: 0.486 Hom.: 8440

Bravo AF: 0.416

Asia WGS AF: 0.179 AC: 627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALDH18A1-related de Barsy syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.63
PhyloP100		0.027
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: rs1053905; hg19: chr10-97366364; COSMIC: COSV64663279; COSMIC: COSV64663279;