rs397514652

Variant names:

• chr15-100887632-C-T
• rs397514652
• NM_000693.4:c.265C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000693.4(ALDH1A3):​c.265C>T​(p.Arg89Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,526 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ALDH1A3 NM_000693.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.47
• Publications: 10 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 Gene-Disease associations (from GenCC):

• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• isolated microphthalmia 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant 15-100887632-C-T is Pathogenic according to our data. Variant chr15-100887632-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 40203.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000693.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	NM_000693.4	MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 3 of 13	NP_000684.2
	ALDH1A3	NM_001293815.2		c.265C>T	p.Arg89Cys	missense	Exon 3 of 10	NP_001280744.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	ENST00000329841.10	TSL:1 MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 3 of 13	ENSP00000332256.5
	ALDH1A3	ENST00000346623.6	TSL:1	c.265C>T	p.Arg89Cys	missense	Exon 3 of 10	ENSP00000343294.6
	ALDH1A3	ENST00000560555.1	TSL:1	n.325C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248780 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459526 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 725990

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39528

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110974

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Isolated microphthalmia 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.54		Gain of catalytic residue at R89 (P = 0.0067)
MVP		0.93
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.85
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs397514652; hg19: chr15-101427837; COSMIC: COSV60900963; COSMIC: COSV60900963;