17-19740386-C-T

Position:

• chr17-19740386-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000691.5(ALDH3A1):​c.899G>A​(p.Gly300Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,614,114 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (74 hom.)
• Consequence: ALDH3A1 NM_000691.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.00

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009444386).
• BP6: Variant 17-19740386-C-T is Benign according to our data. Variant chr17-19740386-C-T is described in ClinVar as [Benign]. Clinvar id is 778684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH3A1	NM_000691.5	c.899G>A	p.Gly300Asp	missense_variant	7/11	ENST00000225740.11	NP_000682.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH3A1	ENST00000225740.11	c.899G>A	p.Gly300Asp	missense_variant	7/11	1	NM_000691.5	ENSP00000225740	P1

Frequencies

GnomAD3 genomes AF: 0.00622 AC: 947 AN: 152170 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00939

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00675 AC: 1696 AN: 251424 Hom.: 16 AF XY: 0.00754 AC XY: 1025 AN XY: 135902

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00630

Gnomad FIN exome AF: 0.000694

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00842 AC: 12309 AN: 1461826 Hom.: 74 Cov.: 30 AF XY: 0.00845 AC XY: 6147 AN XY: 727216

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00636

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00952

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00621 AC: 946 AN: 152288 Hom.: 7 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74466

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00940

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00884 Hom.: 16

Bravo AF: 0.00663

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00728 AC: 884

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;.;T;.;T
MetaRNN	Benign	0.0094	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	.;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.1	.;D;D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.24	.;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.015	.;B;B;B;.
Vest4		0.34
MVP		0.68
MPC		0.65
ClinPred		0.026	T
GERP RS		3.0
Varity_R		0.70
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs142078447; hg19: chr17-19643699; COSMIC: COSV56734758; COSMIC: COSV56734758;