chr3-126135566-T-C

Variant names:

• chr3-126135566-T-C
• rs2276724
• NM_012190.4:c.1441A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012190.4(ALDH1L1):​c.1441A>G​(p.Ser481Gly) variant causes a missense change. The variant allele was found at a frequency of 0.157 in 1,603,936 control chromosomes in the GnomAD database, including 20,493 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1720 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18773 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.78
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016214848).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1L1	NM_012190.4	c.1441A>G	p.Ser481Gly	missense_variant	Exon 12 of 23	ENST00000393434.7	NP_036322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.1441A>G	p.Ser481Gly	missense_variant	Exon 12 of 23	1	NM_012190.4	ENSP00000377083.3

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22587 AN: 152068 Hom.: 1716 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.0919

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.142 AC: 33692 AN: 237286 AF XY: 0.141

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0961

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.157 AC: 228542 AN: 1451750 Hom.: 18773 Cov.: 33 AF XY: 0.155 AC XY: 112067 AN XY: 721882

African (AFR) AF: 0.123 AC: 4067 AN: 33078

American (AMR) AF: 0.0994 AC: 4303 AN: 43280

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3817 AN: 25948

East Asian (EAS) AF: 0.247 AC: 9519 AN: 38572

South Asian (SAS) AF: 0.0810 AC: 6854 AN: 84596

European-Finnish (FIN) AF: 0.132 AC: 6961 AN: 52856

Middle Eastern (MID) AF: 0.145 AC: 833 AN: 5748

European-Non Finnish (NFE) AF: 0.165 AC: 182549 AN: 1107668

Other (OTH) AF: 0.161 AC: 9639 AN: 60004

GnomAD4 genome AF: 0.148 AC: 22599 AN: 152186 Hom.: 1720 Cov.: 32 AF XY: 0.147 AC XY: 10945 AN XY: 74412

African (AFR) AF: 0.130 AC: 5403 AN: 41516

American (AMR) AF: 0.146 AC: 2238 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 504 AN: 3470

East Asian (EAS) AF: 0.219 AC: 1133 AN: 5162

South Asian (SAS) AF: 0.0912 AC: 440 AN: 4826

European-Finnish (FIN) AF: 0.130 AC: 1384 AN: 10606

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10967 AN: 67988

Other (OTH) AF: 0.169 AC: 357 AN: 2116

Alfa AF: 0.159 Hom.: 8620

Bravo AF: 0.149

TwinsUK AF: 0.157 AC: 584

ALSPAC AF: 0.157 AC: 606

ESP6500AA AF: 0.130 AC: 574

ESP6500EA AF: 0.163 AC: 1404

ExAC AF: 0.142 AC: 17200

Asia WGS AF: 0.152 AC: 526 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;.;T;.;T;.
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.045
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.58	T;T;.;T;T;.
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L;.;L;L
PhyloP100		5.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	.;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.052	.;T;T;D;T;D
Sift4G	Uncertain	0.036	D;D;D;T;D;D
Polyphen		0.28	.;.;B;.;B;.
Vest4		0.28
MPC		0.21
ClinPred		0.038	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.29
gMVP		0.46
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2276724; hg19: chr3-125854409; COSMIC: COSV56413444;