rs181000306

Variant names:

• chr3-126107135-C-T
• rs181000306
• NM_012190.4:c.2453+6G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012190.4(ALDH1L1):​c.2453+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00737 in 1,613,134 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (82 hom.)
• Consequence: ALDH1L1 NM_012190.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008391
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0150
• Publications: 0 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]

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-126107135-C-T is Benign according to our data. Variant chr3-126107135-C-T is described in ClinVar as Benign. ClinVar VariationId is 713087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1L1	NM_012190.4	MANE Select	c.2453+6G>A		splice_region intron	N/A	NP_036322.2
	ALDH1L1	NM_001270364.2		c.2483+6G>A		splice_region intron	N/A	NP_001257293.1	O75891-3
	ALDH1L1	NM_001270365.2		c.2150+6G>A		splice_region intron	N/A	NP_001257294.1	O75891-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1L1	ENST00000393434.7	TSL:1 MANE Select	c.2453+6G>A		splice_region intron	N/A	ENSP00000377083.3	O75891-1
	ALDH1L1	ENST00000273450.7	TSL:1	c.2483+6G>A		splice_region intron	N/A	ENSP00000273450.3	O75891-3
	ALDH1L1	ENST00000393431.6	TSL:1	c.*684+6G>A		splice_region intron	N/A	ENSP00000377081.2	O75891-4

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1177 AN: 152234 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00811 AC: 2038 AN: 251392 AF XY: 0.00825

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00733 AC: 10713 AN: 1460782 Hom.: 82 Cov.: 30 AF XY: 0.00735 AC XY: 5343 AN XY: 726726

African (AFR) AF: 0.00111 AC: 37 AN: 33432

American (AMR) AF: 0.00188 AC: 84 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86224

European-Finnish (FIN) AF: 0.0309 AC: 1650 AN: 53364

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00755 AC: 8387 AN: 1111098

Other (OTH) AF: 0.00687 AC: 415 AN: 60366

GnomAD4 genome AF: 0.00773 AC: 1177 AN: 152352 Hom.: 10 Cov.: 33 AF XY: 0.00890 AC XY: 663 AN XY: 74480

African (AFR) AF: 0.00101 AC: 42 AN: 41592

American (AMR) AF: 0.00313 AC: 48 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0318 AC: 338 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 726 AN: 68032

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00725 Hom.: 6

Bravo AF: 0.00467

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00763

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		0.015
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000084
dbscSNV1_RF	Benign	0.074
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

Other links and lift over

dbSNP: rs181000306; hg19: chr3-125825978;