15-100879965-C-G

Variant names:

• chr15-100879965-C-G
• rs888762943
• NM_000693.4:c.58C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000693.4(ALDH1A3):​c.58C>G​(p.Leu20Val) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH1A3 NM_000693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12921903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.58C>G	p.Leu20Val	missense_variant	Exon 1 of 13	ENST00000329841.10	NP_000684.2
ALDH1A3	NM_001293815.2	c.58C>G	p.Leu20Val	missense_variant	Exon 1 of 10		NP_001280744.1
LOC124903575	XM_047433433.1	c.-162G>C		upstream_gene_variant			XP_047289389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.58C>G	p.Leu20Val	missense_variant	Exon 1 of 13	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58C>G (p.L20V) alteration is located in exon 1 (coding exon 1) of the ALDH1A3 gene. This alteration results from a C to G substitution at nucleotide position 58, causing the leucine (L) at amino acid position 20 to be replaced by a valine (V). 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	0.084
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.96	N;D;N
REVEL	Benign	0.082
Sift	Benign	0.49	T;D;T
Sift4G	Benign	0.39	T;D;T
Polyphen		0.31	B;.;.
Vest4		0.25
MutPred		0.23		Loss of catalytic residue at L20 (P = 0.046);Loss of catalytic residue at L20 (P = 0.046);Loss of catalytic residue at L20 (P = 0.046);
MVP		0.37
MPC		0.56
ClinPred		0.18	T
GERP RS		-2.0
Varity_R		0.16
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs888762943; hg19: chr15-101420170;