3-126105748-C-A

Variant names:

• chr3-126105748-C-A
• rs1366124325
• NM_012190.4:c.2631G>T

Variant summary

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

The NM_012190.4(ALDH1L1):​c.2631G>T​(p.Gln877His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.787

Genes affected

ALDH1L1 (HGNC:3978): (aldehyde dehydrogenase 1 family member L1) The protein encoded by this gene catalyzes the conversion of 10-formyltetrahydrofolate, nicotinamide adenine dinucleotide phosphate (NADP+), and water to tetrahydrofolate, NADPH, and carbon dioxide. The encoded protein belongs to the aldehyde dehydrogenase family. Loss of function or expression of this gene is associated with decreased apoptosis, increased cell motility, and cancer progression. There is an antisense transcript that overlaps on the opposite strand with this gene locus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ALDH1L1-AS1 (HGNC:40244): (ALDH1L1 antisense RNA 1)

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 rank	MANE	Protein	UniProt
ALDH1L1	NM_012190.4	c.2631G>T	p.Gln877His	missense_variant	Exon 22 of 23	ENST00000393434.7	NP_036322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.2631G>T	p.Gln877His	missense_variant	Exon 22 of 23	1	NM_012190.4	ENSP00000377083.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2631G>T (p.Q877H) alteration is located in exon 22 (coding exon 21) of the ALDH1L1 gene. This alteration results from a G to T substitution at nucleotide position 2631, causing the glutamine (Q) at amino acid position 877 to be replaced by a histidine (H). 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	0.72
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Uncertain	2.3	.;M;.;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.61
MutPred		0.62		.;Loss of glycosylation at S878 (P = 0.0218);.;Loss of glycosylation at S878 (P = 0.0218);
MVP		0.81
MPC		0.72
ClinPred		0.98	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.68
gMVP		0.80

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: rs1366124325; hg19: chr3-125824591;