15-100885370-A-C

Position:

• chr15-100885370-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000693.4(ALDH1A3):​c.203A>C​(p.Lys68Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH1A3 NM_000693.4 missense, splice_region
• Scores: Splicing: ADA: 0.9875
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.93

Genes affected

ALDH1A3 (HGNC:409): (aldehyde dehydrogenase 1 family member A3) This gene encodes an aldehyde dehydrogenase enzyme that uses retinal as a substrate. Mutations in this gene have been associated with microphthalmia, isolated 8, and expression changes have also been detected in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ENSG00000272639 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.203A>C	p.Lys68Thr	missense_variant, splice_region_variant	2/13	ENST00000329841.10	NP_000684.2
ALDH1A3	NM_001293815.2	c.203A>C	p.Lys68Thr	missense_variant, splice_region_variant	2/10		NP_001280744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.203A>C	p.Lys68Thr	missense_variant, splice_region_variant	2/13	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.203A>C (p.K68T) alteration is located in exon 2 (coding exon 2) of the ALDH1A3 gene. This alteration results from a A to C substitution at nucleotide position 203, causing the lysine (K) at amino acid position 68 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	1.2	.;L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.98	.;D;.
Vest4		0.59, 0.60
MutPred		0.45		.;Gain of phosphorylation at K68 (P = 0.0102);Gain of phosphorylation at K68 (P = 0.0102);
MVP		0.79
MPC		1.6
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.020		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: chr15-101425575;