NM_000382.3:c.3G>C

Variant names:

• chr17-19648974-G-C
• rs2084774156
• NM_000382.3:c.3G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000382.3(ALDH3A2):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ALDH3A2 NM_000382.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.44

Genes affected

ALDH3A2 (HGNC:403): (aldehyde dehydrogenase 3 family member A2) Aldehyde dehydrogenase isozymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This gene product catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid. Mutations in the gene cause Sjogren-Larsson syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 33 codons. Genomic position: 19649068. Lost 0.067 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-19648974-G-C is Pathogenic according to our data. Variant chr17-19648974-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH3A2	NM_000382.3	c.3G>C	p.Met1?	start_lost	Exon 1 of 10	ENST00000176643.11	NP_000373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH3A2	ENST00000176643.11	c.3G>C	p.Met1?	start_lost	Exon 1 of 10	1	NM_000382.3	ENSP00000176643.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434772 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 711202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:1

Jul 05, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the ALDH3A2 mRNA. The next in-frame methionine is located at codon 33. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALDH3A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 552722). This variant disrupts a region of the ALDH3A2 protein in which other variant(s) (p.Leu27Pro) have been determined to be pathogenic (PMID: 11408337). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0055	.;T;.;.;T;.;T;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
PROVEAN	Benign	-1.1	N;.;.;.;N;.;N;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.035	D;.;.;.;D;.;D;D;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T
Polyphen		0.97, 0.99	.;.;.;.;D;D;D;D;D
Vest4		0.46, 0.77, 0.76, 0.50, 0.78, 0.80, 0.76
MutPred		0.89		Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);Loss of methylation at R6 (P = 0.1612);
MVP		0.90
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.78
gMVP		0.42

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: rs2084774156; hg19: chr17-19552287;