10-95616339-A-T

Variant names:

• chr10-95616339-A-T
• rs749049
• NM_002860.4:c.1605+138T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002860.4(ALDH18A1):​c.1605+138T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,238,366 control chromosomes in the GnomAD database, including 152,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (18022 hom., cov: 33)
  • Exomes 𝑓: 0.49 (134759 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.639
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-95616339-A-T is Benign according to our data. Variant chr10-95616339-A-T is described in ClinVar as Benign. ClinVar VariationId is 1230894.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4	c.1605+138T>A		intron_variant	Intron 13 of 17	ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.1605+138T>A		intron_variant	Intron 13 of 17	1	NM_002860.4	ENSP00000360268.2
ALDH18A1	ENST00000371221.3	c.1599+138T>A		intron_variant	Intron 13 of 17	1		ENSP00000360265.3
ALDH18A1	ENST00000485428.1	n.221+138T>A		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73670 AN: 152032 Hom.: 18031 Cov.: 33

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.492

GnomAD4 exome AF: 0.493 AC: 535853 AN: 1086214 Hom.: 134759 AF XY: 0.492 AC XY: 268433 AN XY: 545510

African (AFR) AF: 0.470 AC: 11933 AN: 25396

American (AMR) AF: 0.565 AC: 18672 AN: 33040

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 11309 AN: 21796

East Asian (EAS) AF: 0.233 AC: 7979 AN: 34206

South Asian (SAS) AF: 0.451 AC: 31116 AN: 68966

European-Finnish (FIN) AF: 0.416 AC: 15174 AN: 36478

Middle Eastern (MID) AF: 0.543 AC: 1860 AN: 3424

European-Non Finnish (NFE) AF: 0.508 AC: 414016 AN: 815386

Other (OTH) AF: 0.501 AC: 23794 AN: 47522

GnomAD4 genome AF: 0.484 AC: 73682 AN: 152152 Hom.: 18022 Cov.: 33 AF XY: 0.481 AC XY: 35788 AN XY: 74384

African (AFR) AF: 0.473 AC: 19639 AN: 41508

American (AMR) AF: 0.542 AC: 8287 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1768 AN: 3472

East Asian (EAS) AF: 0.253 AC: 1312 AN: 5178

South Asian (SAS) AF: 0.439 AC: 2119 AN: 4828

European-Finnish (FIN) AF: 0.422 AC: 4463 AN: 10580

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.506 AC: 34375 AN: 67984

Other (OTH) AF: 0.489 AC: 1031 AN: 2110

Alfa AF: 0.489 Hom.: 2269

Bravo AF: 0.494

Asia WGS AF: 0.335 AC: 1168 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.73
PhyloP100		-0.64
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: rs749049; hg19: chr10-97376096;