NM_000691.5:c.980A>C

Variant names:

• chr17-19739644-T-G
• NM_000691.5:c.980A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000691.5(ALDH3A1):​c.980A>C​(p.Gln327Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ALDH3A1 NM_000691.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54
• Publications: 0 publications found

Genes affected

ALDH3A1 (HGNC:405): (aldehyde dehydrogenase 3 family member A1) Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-derived acetaldehyde and in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. The enzyme encoded by this gene forms a cytoplasmic homodimer that preferentially oxidizes aromatic and medium-chain (6 carbons or more) saturated and unsaturated aldehyde substrates. It is thought to promote resistance to UV and 4-hydroxy-2-nonenal-induced oxidative damage in the cornea. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27791733).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000691.5. 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
	ALDH3A1	NM_000691.5	MANE Select	c.980A>C	p.Gln327Pro	missense	Exon 8 of 11	NP_000682.3
	ALDH3A1	NM_001135167.1		c.980A>C	p.Gln327Pro	missense	Exon 8 of 11	NP_001128639.1	P30838
	ALDH3A1	NM_001135168.1		c.980A>C	p.Gln327Pro	missense	Exon 7 of 10	NP_001128640.1	P30838

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A1	ENST00000225740.11	TSL:1 MANE Select	c.980A>C	p.Gln327Pro	missense	Exon 8 of 11	ENSP00000225740.6	P30838
	ALDH3A1	ENST00000457500.6	TSL:1	c.980A>C	p.Gln327Pro	missense	Exon 7 of 10	ENSP00000411821.2	P30838
	ALDH3A1	ENST00000905965.1		c.1001A>C	p.Gln334Pro	missense	Exon 8 of 11	ENSP00000576024.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461576 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727066

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.29
Sift	Benign	0.14	T
Sift4G	Uncertain	0.032	D
Polyphen		0.029	B
Vest4		0.35
MutPred		0.48		Gain of catalytic residue at P326 (P = 0.0218)
MVP		0.64
MPC		0.32
ClinPred		0.15	T
GERP RS		1.1
Varity_R		0.92
gMVP		0.82
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr17-19642957;