rs3765571

Variant names:

• chr10-95626740-G-T
• rs3765571
• NM_002860.4:c.1115C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-95626740-G-T
• chr10-95626740-G-A
• chr10-95626740-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002860.4(ALDH18A1):​c.1115C>A​(p.Ser372Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,613,874 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 32)
  • Exomes 𝑓: 0.019 (311 hom.)
• Consequence: ALDH18A1 NM_002860.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.29
• Publications: 17 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 (MetaRNN=0.0072588027).
• BP6: Variant 10-95626740-G-T is Benign according to our data. Variant chr10-95626740-G-T is described in ClinVar as Benign. ClinVar VariationId is 301770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0149 (2271/152178) while in subpopulation EAS AF = 0.0376 (194/5158). AF 95% confidence interval is 0.0333. There are 29 homozygotes in GnomAd4. There are 1098 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR,AD,SD gene

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.1115C>A	p.Ser372Tyr	missense	Exon 10 of 18	NP_002851.2
	ALDH18A1	NM_001323413.2		c.1115C>A	p.Ser372Tyr	missense	Exon 10 of 18	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.1115C>A	p.Ser372Tyr	missense	Exon 10 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.1115C>A	p.Ser372Tyr	missense	Exon 10 of 18	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.1109C>A	p.Ser370Tyr	missense	Exon 10 of 18	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.1115C>A	p.Ser372Tyr	missense	Exon 10 of 18	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2274 AN: 152060 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00650

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0174 AC: 4382 AN: 251460 AF XY: 0.0187

Gnomad AFR exome AF: 0.00547

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.0377

Gnomad FIN exome AF: 0.00457

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0191 AC: 27955 AN: 1461696 Hom.: 311 Cov.: 31 AF XY: 0.0195 AC XY: 14157 AN XY: 727162

African (AFR) AF: 0.00624 AC: 209 AN: 33478

American (AMR) AF: 0.00917 AC: 410 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 748 AN: 26128

East Asian (EAS) AF: 0.0361 AC: 1434 AN: 39698

South Asian (SAS) AF: 0.0169 AC: 1454 AN: 86256

European-Finnish (FIN) AF: 0.00468 AC: 250 AN: 53408

Middle Eastern (MID) AF: 0.0343 AC: 198 AN: 5768

European-Non Finnish (NFE) AF: 0.0199 AC: 22097 AN: 1111852

Other (OTH) AF: 0.0191 AC: 1155 AN: 60388

GnomAD4 genome AF: 0.0149 AC: 2271 AN: 152178 Hom.: 29 Cov.: 32 AF XY: 0.0148 AC XY: 1098 AN XY: 74424

African (AFR) AF: 0.00648 AC: 269 AN: 41506

American (AMR) AF: 0.0141 AC: 215 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3470

East Asian (EAS) AF: 0.0376 AC: 194 AN: 5158

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4826

European-Finnish (FIN) AF: 0.00387 AC: 41 AN: 10596

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0190 AC: 1290 AN: 68016

Other (OTH) AF: 0.0242 AC: 51 AN: 2108

Alfa AF: 0.0194 Hom.: 136

Bravo AF: 0.0154

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0193 AC: 166

ExAC AF: 0.0172 AC: 2093

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0241

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	ALDH18A1-related de Barsy syndrome (2)
-	-	1	Cutis laxa, autosomal dominant 3;C5234852:ALDH18A1-related de Barsy syndrome;C5568978:Hereditary spastic paraplegia 9A;C5568980:Autosomal recessive complex spastic paraplegia type 9B (1)
-	-	1	de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.29
Sift	Benign	0.038	D
Sift4G	Uncertain	0.047	D
Polyphen		0.021	B
Vest4		0.14
MPC		0.37
ClinPred		0.034	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.53
Mutation Taster		=91/9	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: rs3765571; hg19: chr10-97386497; COSMIC: COSV64663964;