chr17-19648974-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ALDH3A2 NM_000382.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.44
• Publications: 0 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 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 Pathogenic. ClinVar VariationId is 552722.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3G>C	p.Met1?	start_lost	Exon 1 of 10	NP_000373.1	P51648-1
	ALDH3A2	NM_001031806.2		c.3G>C	p.Met1?	start_lost	Exon 1 of 11	NP_001026976.1	P51648-2
	ALDH3A2	NM_001369136.1		c.3G>C	p.Met1?	start_lost	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.3G>C	p.Met1?	start_lost	Exon 1 of 10	ENSP00000176643.6	P51648-1
	ALDH3A2	ENST00000339618.8	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 11	ENSP00000345774.4	P51648-2
	ALDH3A2	ENST00000671878.1		c.3G>C	p.Met1?	start_lost	Exon 1 of 10	ENSP00000500516.1	A0A5F9ZHN9

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

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.00 AC: 0 AN: 40478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.00 AC: 0 AN: 38824

South Asian (SAS) AF: 0.00 AC: 0 AN: 82270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099684

Other (OTH) AF: 0.00 AC: 0 AN: 59286

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Sjögren-Larsson syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.28	T
PhyloP100		1.4
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.50
Sift	Benign	0.035	D
Sift4G	Benign	0.19	T
Polyphen		0.97	D
Vest4		0.46
MutPred		0.89		Loss of methylation at R6 (P = 0.1612)
MVP		0.90
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.78
gMVP		0.42
Mutation Taster		=17/183	disease causing (ClinVar)

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: rs2084774156; hg19: chr17-19552287;