17-19648972-A-T

Position:

• chr17-19648972-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000382.3(ALDH3A2):​c.1A>T​(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 1,434,148 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ALDH3A2 NM_000382.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000382.3 (ALDH3A2) was described as [Likely_pathogenic] in ClinVar as 552722
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-19648972-A-T is Pathogenic according to our data. Variant chr17-19648972-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH3A2	NM_000382.3	c.1A>T	p.Met1?	start_lost	1/10	ENST00000176643.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH3A2	ENST00000176643.11	c.1A>T	p.Met1?	start_lost	1/10	1	NM_000382.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434148 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 710836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sjögren-Larsson syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2023	Variant summary: ALDH3A2 c.1A>T (p.Met1?, aka p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The first potential downstream in-frame start codon (ATG) is located in the same exon, at Met33. Several other start-lost variants, and truncations upstream from Met33 have been reported in individuals affected with Sjogren-Larsson Syndrome (HGMD). The variant was absent in 201014 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1A>T in individuals affected with Sjogren-Larsson Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.0060	.;T;.;.;T;.;T;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-0.82	N;.;.;.;N;.;N;N;.
REVEL	Uncertain	0.58
Sift	Benign	0.099	T;.;.;.;D;.;D;D;.
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T
Polyphen		0.88, 0.93	.;.;.;.;P;P;P;P;P
Vest4		0.48, 0.74, 0.74, 0.61, 0.74, 0.86, 0.72
MutPred		0.87		Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);Gain of methylation at R6 (P = 0.1297);
MVP		0.89
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.83
gMVP		0.41

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-19552285;