12-105026736-T-G

Position:

• chr12-105026736-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001034173.4(ALDH1L2):​c.2525A>C​(p.Asp842Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH1L2 NM_001034173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1L2	NM_001034173.4	c.2525A>C	p.Asp842Ala	missense_variant	22/23	ENST00000258494.14
ALDH1L2	XM_047428406.1	c.2186A>C	p.Asp729Ala	missense_variant	22/23
ALDH1L2	XM_047428407.1	c.2087A>C	p.Asp696Ala	missense_variant	21/22
ALDH1L2	NR_027752.2	n.2499A>C		non_coding_transcript_exon_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1L2	ENST00000258494.14	c.2525A>C	p.Asp842Ala	missense_variant	22/23	1	NM_001034173.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

May 17, 2023

The c.2525A>C (p.D842A) alteration is located in exon 22 (coding exon 22) of the ALDH1L2 gene. This alteration results from a A to C substitution at nucleotide position 2525, causing the aspartic acid (D) at amino acid position 842 to be replaced by an alanine (A). 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	Benign	0.097
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.064	T
Polyphen		0.41	B
Vest4		0.67
MutPred		0.69		Loss of loop (P = 0.0203);
MVP		0.44
MPC		0.70
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.74
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-105420514;