rs730880264

Variant names:

• chr17-19663333-CCC-GGGCTAAAAGTACTGTTGGGG
• rs730880264
• NM_000382.3:c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM4 PP3 PP5_Very_Strong

The NM_000382.3(ALDH3A2):​c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG​(p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla) variant causes a missense, disruptive inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002819866: At least two publications report that FALDH activity in patients carrying this variant is <10% of normal activity." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A314A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH3A2 NM_000382.3 missense, disruptive_inframe_insertion, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.83
• Publications: 1 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002819866: At least two publications report that FALDH activity in patients carrying this variant is <10% of normal activity.; SCV005400581: This variant has moderate functional evidence supporting abnormal protein function. An individual homozygous for this variant was shown to have 8% of mean ALDH3A2 activity and their heterozygous parents had 39% and 47% of mean activity (PMID: 8528251).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000382.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000382.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-19663333-CCC-GGGCTAAAAGTACTGTTGGGG is Pathogenic according to our data. Variant chr17-19663333-CCC-GGGCTAAAAGTACTGTTGGGG is described in ClinVar as Pathogenic. ClinVar VariationId is 1638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG	p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla	missense disruptive_inframe_insertion splice_region	N/A	NP_000373.1	P51648-1
	ALDH3A2	NM_001031806.2		c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG	p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla	missense disruptive_inframe_insertion splice_region	N/A	NP_001026976.1	P51648-2
	ALDH3A2	NM_001369136.1		c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG	p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla	missense disruptive_inframe_insertion splice_region	N/A	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.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG	p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla	missense disruptive_inframe_insertion splice_region	N/A	ENSP00000176643.6	P51648-1
	ALDH3A2	ENST00000339618.8	TSL:1	c.941_943delCCCinsGGGCTAAAAGTACTGTTGGGG	p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla	missense disruptive_inframe_insertion splice_region	N/A	ENSP00000345774.4	P51648-2
	ALDH3A2	ENST00000476965.5	TSL:1	n.691_693delCCCinsGGGCTAAAAGTACTGTTGGGG		splice_region non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Sjögren-Larsson syndrome (4)
1	-	-	Cerebral palsy (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730880264; hg19: chr17-19566646;