15-100905610-A-C

Variant names:

• chr15-100905610-A-C
• rs3803430
• NM_000693.4:c.1156A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_000693.4(ALDH1A3):​c.1156A>C​(p.Met386Leu) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M386V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH1A3 NM_000693.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.161
• Publications: 21 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.2359 (below the threshold of 3.09). Trascript score misZ: 2.2507 (below the threshold of 3.09). GenCC associations: The gene is linked to isolated anophthalmia-microphthalmia syndrome, isolated microphthalmia 8.
• BP4: Computational evidence support a benign effect (MetaRNN=0.016959488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.1156A>C	p.Met386Leu	missense_variant	Exon 10 of 13	ENST00000329841.10	NP_000684.2
ALDH1A3	NM_001293815.2	c.835A>C	p.Met279Leu	missense_variant	Exon 7 of 10		NP_001280744.1
ALDH1A3-AS1	NR_135827.1	n.481-9544T>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.1156A>C	p.Met386Leu	missense_variant	Exon 10 of 13	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2268

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.14
DANN	Benign	0.63
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.0	N;.
PhyloP100		-0.16
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.16
Sift	Benign	0.65	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0010	B;.
Vest4		0.13
MutPred		0.20		Loss of ubiquitination at K389 (P = 0.047);.;
MVP		0.24
MPC		0.52
ClinPred		0.040	T
GERP RS		-1.3
Varity_R		0.16
gMVP		0.46

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

Other links and lift over

dbSNP: rs3803430; hg19: chr15-101445815;