3-126114595-T-C

Position:

• chr3-126114595-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012190.4(ALDH1L1):​c.2044A>G​(p.Ile682Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37059742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1L1	NM_012190.4	c.2044A>G	p.Ile682Val	missense_variant	18/23	ENST00000393434.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.2044A>G	p.Ile682Val	missense_variant	18/23	1	NM_012190.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 13, 2022

The c.2044A>G (p.I682V) alteration is located in exon 18 (coding exon 17) of the ALDH1L1 gene. This alteration results from a A to G substitution at nucleotide position 2044, causing the isoleucine (I) at amino acid position 682 to be replaced by a valine (V). 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	0.098
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T;.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.77	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		1.0	.;D;.;D
Vest4		0.32
MutPred		0.42		.;Gain of catalytic residue at I682 (P = 0.0266);.;Gain of catalytic residue at I682 (P = 0.0266);
MVP		0.57
MPC		0.15
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.13
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-125833438;