12-105034376-T-G

Position:

• chr12-105034376-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001034173.4(ALDH1L2):​c.2168A>C​(p.Asn723Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,611,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: ALDH1L2 NM_001034173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH1L2	NM_001034173.4	c.2168A>C	p.Asn723Thr	missense_variant	19/23	ENST00000258494.14	NP_001029345.2
ALDH1L2	XM_047428406.1	c.1829A>C	p.Asn610Thr	missense_variant	19/23		XP_047284362.1
ALDH1L2	XM_047428407.1	c.1730A>C	p.Asn577Thr	missense_variant	18/22		XP_047284363.1
ALDH1L2	NR_027752.2	n.2186A>C		non_coding_transcript_exon_variant	19/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH1L2	ENST00000258494.14	c.2168A>C	p.Asn723Thr	missense_variant	19/23	1	NM_001034173.4	ENSP00000258494	P1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000316 AC: 78 AN: 246922 Hom.: 0 AF XY: 0.000262 AC XY: 35 AN XY: 133386

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000658

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000602 AC: 878 AN: 1458706 Hom.: 0 Cov.: 31 AF XY: 0.000572 AC XY: 415 AN XY: 725524

Gnomad4 AFR exome AF: 0.0000904

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000703

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000756

Gnomad4 OTH exome AF: 0.000415

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74500

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000494 Hom.: 1

Bravo AF: 0.000348

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000280 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000535

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

Jul 08, 2022

The c.2168A>C (p.N723T) alteration is located in exon 19 (coding exon 19) of the ALDH1L2 gene. This alteration results from a A to C substitution at nucleotide position 2168, causing the asparagine (N) at amino acid position 723 to be replaced by a threonine (T). 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	0.96
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.60
MPC		0.71
ClinPred		0.37	T
GERP RS		5.4
Varity_R		0.88
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs143839661; hg19: chr12-105428154;