rs1127717

Positions:

• chr3-126107216-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012190.4(ALDH1L1):​c.2378A>G​(p.Asp793Gly) variant causes a missense change. The variant allele was found at a frequency of 0.202 in 1,613,530 control chromosomes in the GnomAD database, including 33,783 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3102 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30681 hom.)
• Consequence: ALDH1L1 NM_012190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.98

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026737452).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1L1	NM_012190.4	c.2378A>G	p.Asp793Gly	missense_variant	21/23	ENST00000393434.7
ALDH1L1-AS1	NR_046602.1	n.252-668T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1L1	ENST00000393434.7	c.2378A>G	p.Asp793Gly	missense_variant	21/23	1	NM_012190.4	P1
ALDH1L1-AS1	ENST00000512384.1	n.252-668T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30131 AN: 152116 Hom.: 3099 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.185 AC: 46395 AN: 251432 Hom.: 4650 AF XY: 0.190 AC XY: 25832 AN XY: 135886

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.202 AC: 295779 AN: 1461296 Hom.: 30681 Cov.: 33 AF XY: 0.204 AC XY: 148333 AN XY: 727016

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.198 AC: 30142 AN: 152234 Hom.: 3102 Cov.: 33 AF XY: 0.194 AC XY: 14412 AN XY: 74432

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.232

Alfa AF: 0.208 Hom.: 8307

Bravo AF: 0.202

TwinsUK AF: 0.201 AC: 746

ALSPAC AF: 0.199 AC: 767

ESP6500AA AF: 0.213 AC: 940

ESP6500EA AF: 0.216 AC: 1855

ExAC AF: 0.189 AC: 22887

Asia WGS AF: 0.210 AC: 729 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.222

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.68	T;.;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0030	.;B;.;B
Vest4		0.14
MPC		0.25
ClinPred		0.019	T
GERP RS		4.0
Varity_R		0.30
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1127717; hg19: chr3-125826059; COSMIC: COSV56412084;