rs72547572

Variant names:

• chr17-19663376-G-A
• rs72547572
• NM_000382.3:c.984G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-19663376-G-A
• chr17-19663376-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000382.3(ALDH3A2):​c.984G>A​(p.Met328Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,224 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 Uncertain significance (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ALDH3A2 NM_000382.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.90
• Publications: 2 publications found

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]

ALDH3A2 Gene-Disease associations (from GenCC):

• Sjogren-Larsson syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH3A2	NM_000382.3	c.984G>A	p.Met328Ile	missense_variant	Exon 7 of 10	ENST00000176643.11	NP_000373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH3A2	ENST00000176643.11	c.984G>A	p.Met328Ile	missense_variant	Exon 7 of 10	1	NM_000382.3	ENSP00000176643.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Sjögren-Larsson syndrome Uncertain:1

May 22, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.;D;.;D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;.;.;D;.;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.3	.;M;M;M;M;M;.;.
PhyloP100		9.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	.;D;.;D;D;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.017	.;D;.;D;D;.;.;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;D;D;.;.
Vest4		0.88
MutPred		0.90		Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);Gain of methylation at K324 (P = 0.1005);.;.;
MVP		0.99
MPC		0.86
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		-0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.87

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

Other links and lift over

dbSNP: rs72547572; hg19: chr17-19566689;