10-95610243-G-A

Variant names:

• chr10-95610243-G-A
• rs374052426
• NM_002860.4:c.2160C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_002860.4(ALDH18A1):​c.2160C>T​(p.Phe720Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.000734 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: ALDH18A1 NM_002860.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.44
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 10-95610243-G-A is Benign according to our data. Variant chr10-95610243-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392692.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00065 (99/152208) while in subpopulation AMR AF = 0.00118 (18/15274). AF 95% confidence interval is 0.000808. There are 1 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2160C>T	p.Phe720Phe	synonymous	Exon 17 of 18	NP_002851.2
	ALDH18A1	NM_001323413.2		c.2160C>T	p.Phe720Phe	synonymous	Exon 17 of 18	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.2160C>T	p.Phe720Phe	synonymous	Exon 17 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.2160C>T	p.Phe720Phe	synonymous	Exon 17 of 18	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.2154C>T	p.Phe718Phe	synonymous	Exon 17 of 18	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.2160C>T	p.Phe720Phe	synonymous	Exon 17 of 18	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000434 AC: 109 AN: 251326 AF XY: 0.000383

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000743 AC: 1086 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.000704 AC XY: 512 AN XY: 727192

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000537 AC: 24 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53404

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000927 AC: 1031 AN: 1111958

Other (OTH) AF: 0.000348 AC: 21 AN: 60384

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.000592 AC XY: 44 AN XY: 74358

African (AFR) AF: 0.000217 AC: 9 AN: 41464

American (AMR) AF: 0.00118 AC: 18 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68030

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.000567

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		4.4
Mutation Taster		=99/1	polymorphism

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: rs374052426; hg19: chr10-97370000;