chr15-100895963-G-A

Position:

• chr15-100895963-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000693.4(ALDH1A3):​c.697G>A​(p.Val233Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH1A3 NM_000693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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]

ALDH1A3-AS1 (HGNC:55416): (ALDH1A3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH1A3	NM_000693.4	c.697G>A	p.Val233Met	missense_variant	7/13	ENST00000329841.10
ALDH1A3-AS1	NR_135827.1	n.584C>T		non_coding_transcript_exon_variant	2/2
ALDH1A3	NM_001293815.2	c.376G>A	p.Val126Met	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.697G>A	p.Val233Met	missense_variant	7/13	1	NM_000693.4	P1
ALDH1A3-AS1	ENST00000656756.1	n.692C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Dec 21, 2023

The c.697G>A (p.V233M) alteration is located in exon 7 (coding exon 7) of the ALDH1A3 gene. This alteration results from a G to A substitution at nucleotide position 697, causing the valine (V) at amino acid position 233 to be replaced by a methionine (M). 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.97	D;.
Vest4		0.70
MutPred		0.81		Loss of catalytic residue at V233 (P = 0.1075);.;
MVP		0.45
MPC		1.3
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.79

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: chr15-101436168;