12-105026703-T-C

Position:

• chr12-105026703-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001034173.4(ALDH1L2):​c.2558A>G​(p.Tyr853Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,868 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: ALDH1L2 NM_001034173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

Genes affected

ALDH1L2 (HGNC:26777): (aldehyde dehydrogenase 1 family member L2) This gene encodes a member of both the aldehyde dehydrogenase superfamily and the formyl transferase superfamily. This member is the mitochondrial form of 10-formyltetrahydrofolate dehydrogenase (FDH), which converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in an NADP(+)-dependent reaction, and plays an essential role in the distribution of one-carbon groups between the cytosolic and mitochondrial compartments of the cell. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Oct 2010]

NOPCHAP1 (HGNC:28628): (NOP protein chaperone 1) Enables box C/D snoRNP complex binding activity. Involved in box C/D snoRNP assembly. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ALDH1L2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH1L2	NM_001034173.4	c.2558A>G	p.Tyr853Cys	missense_variant	22/23	ENST00000258494.14	NP_001029345.2
ALDH1L2	XM_047428406.1	c.2219A>G	p.Tyr740Cys	missense_variant	22/23		XP_047284362.1
ALDH1L2	XM_047428407.1	c.2120A>G	p.Tyr707Cys	missense_variant	21/22		XP_047284363.1
ALDH1L2	NR_027752.2	n.2532A>G		non_coding_transcript_exon_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH1L2	ENST00000258494.14	c.2558A>G	p.Tyr853Cys	missense_variant	22/23	1	NM_001034173.4	ENSP00000258494.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

The c.2558A>G (p.Y853C) alteration is located in exon 22 (coding exon 22) of the ALDH1L2 gene. This alteration results from a A to G substitution at nucleotide position 2558, causing the tyrosine (Y) at amino acid position 853 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.89		Loss of disorder (P = 0.0997);
MVP		0.89
MPC		0.79
ClinPred		1.0	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1874427876; hg19: chr12-105420481;