rs72547554

Variant names:

• chr17-19648999-C-G
• rs72547554
• NM_000382.3:c.28C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-19648999-C-G
• chr17-19648999-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000382.3(ALDH3A2):​c.28C>G​(p.Gln10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,585,796 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q10L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (24 hom.)
• Consequence: ALDH3A2 NM_000382.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.770
• Publications: 8 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: Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008210927).
• BP6: Variant 17-19648999-C-G is Benign according to our data. Variant chr17-19648999-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 495853.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00403 (614/152352) while in subpopulation NFE AF = 0.00711 (484/68034). AF 95% confidence interval is 0.00659. There are 1 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000382.3. 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
	ALDH3A2	NM_000382.3	MANE Select	c.28C>G	p.Gln10Glu	missense	Exon 1 of 10	NP_000373.1	P51648-1
	ALDH3A2	NM_001031806.2		c.28C>G	p.Gln10Glu	missense	Exon 1 of 11	NP_001026976.1	P51648-2
	ALDH3A2	NM_001369136.1		c.28C>G	p.Gln10Glu	missense	Exon 2 of 12	NP_001356065.1	P51648-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH3A2	ENST00000176643.11	TSL:1 MANE Select	c.28C>G	p.Gln10Glu	missense	Exon 1 of 10	ENSP00000176643.6	P51648-1
	ALDH3A2	ENST00000339618.8	TSL:1	c.28C>G	p.Gln10Glu	missense	Exon 1 of 11	ENSP00000345774.4	P51648-2
	ALDH3A2	ENST00000671878.1		c.28C>G	p.Gln10Glu	missense	Exon 1 of 10	ENSP00000500516.1	A0A5F9ZHN9

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00711

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00361 AC: 702 AN: 194412 AF XY: 0.00379

Gnomad AFR exome AF: 0.000971

Gnomad AMR exome AF: 0.000802

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00355

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00563 AC: 8066 AN: 1433444 Hom.: 24 Cov.: 30 AF XY: 0.00553 AC XY: 3928 AN XY: 710452

African (AFR) AF: 0.000903 AC: 30 AN: 33220

American (AMR) AF: 0.000899 AC: 36 AN: 40066

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 40 AN: 25382

East Asian (EAS) AF: 0.00 AC: 0 AN: 38682

South Asian (SAS) AF: 0.000571 AC: 47 AN: 82336

European-Finnish (FIN) AF: 0.00417 AC: 209 AN: 50140

Middle Eastern (MID) AF: 0.000362 AC: 2 AN: 5530

European-Non Finnish (NFE) AF: 0.00680 AC: 7470 AN: 1098822

Other (OTH) AF: 0.00391 AC: 232 AN: 59266

GnomAD4 genome AF: 0.00403 AC: 614 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.00374 AC XY: 279 AN XY: 74506

African (AFR) AF: 0.00137 AC: 57 AN: 41586

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00711 AC: 484 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00285 Hom.: 2

Bravo AF: 0.00357

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000692 AC: 3

ESP6500EA AF: 0.00648 AC: 55

ExAC AF: 0.00344 AC: 411

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	ALDH3A2-related disorder (1)
-	1	-	Sjögren-Larsson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.69
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N
PhyloP100		0.77
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.085
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.073
MVP		0.60
MPC		0.25
ClinPred		0.0029	T
GERP RS		2.2
PromoterAI		0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.15
Mutation Taster		=100/0	polymorphism

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: rs72547554; hg19: chr17-19552312; COSMIC: COSV99449841; COSMIC: COSV99449841;