10-95611185-G-C

Variant names:

• chr10-95611185-G-C
• rs2296690
• NM_002860.4:c.2110+71C>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.2110+71C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,573,114 control chromosomes in the GnomAD database, including 12,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1031 hom., cov: 33)
  • Exomes 𝑓: 0.13 (11814 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.251
• Publications: 2 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=-0.83).
• BP6: Variant 10-95611185-G-C is Benign according to our data. Variant chr10-95611185-G-C is described in ClinVar as Benign. ClinVar VariationId is 1242768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH18A1	NM_002860.4	MANE Select	c.2110+71C>G		intron	N/A	NP_002851.2
	ALDH18A1	NM_001323413.2		c.2110+71C>G		intron	N/A	NP_001310342.1
	ALDH18A1	NM_001323414.2		c.2110+71C>G		intron	N/A	NP_001310343.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH18A1	ENST00000371224.7	TSL:1 MANE Select	c.2110+71C>G		intron	N/A	ENSP00000360268.2
	ALDH18A1	ENST00000371221.3	TSL:1	c.2104+71C>G		intron	N/A	ENSP00000360265.3
	ALDH18A1	ENST00000485428.1	TSL:2	n.*71C>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16141 AN: 152114 Hom.: 1031 Cov.: 33

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0408

Gnomad SAS AF: 0.0731

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.126 AC: 178576 AN: 1420882 Hom.: 11814 AF XY: 0.125 AC XY: 88721 AN XY: 708410

African (AFR) AF: 0.0447 AC: 1456 AN: 32602

American (AMR) AF: 0.0753 AC: 3361 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5185 AN: 25868

East Asian (EAS) AF: 0.0374 AC: 1472 AN: 39402

South Asian (SAS) AF: 0.0796 AC: 6784 AN: 85226

European-Finnish (FIN) AF: 0.159 AC: 8487 AN: 53216

Middle Eastern (MID) AF: 0.178 AC: 765 AN: 4286

European-Non Finnish (NFE) AF: 0.133 AC: 143680 AN: 1076746

Other (OTH) AF: 0.125 AC: 7386 AN: 58910

GnomAD4 genome AF: 0.106 AC: 16136 AN: 152232 Hom.: 1031 Cov.: 33 AF XY: 0.105 AC XY: 7843 AN XY: 74416

African (AFR) AF: 0.0490 AC: 2036 AN: 41556

American (AMR) AF: 0.100 AC: 1535 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3468

East Asian (EAS) AF: 0.0411 AC: 213 AN: 5186

South Asian (SAS) AF: 0.0732 AC: 353 AN: 4824

European-Finnish (FIN) AF: 0.154 AC: 1633 AN: 10596

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9213 AN: 67998

Other (OTH) AF: 0.129 AC: 272 AN: 2112

Alfa AF: 0.0417 Hom.: 48

Bravo AF: 0.101

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2296690; hg19: chr10-97370942; COSMIC: COSV64663761; COSMIC: COSV64663761;