15-100885498-T-G

Variant names:

• chr15-100885498-T-G
• rs4646656
• NM_000693.4:c.204+127T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000693.4(ALDH1A3):​c.204+127T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000203 in 492,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 0 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: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• isolated microphthalmia 8

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	NM_000693.4	MANE Select	c.204+127T>G		intron	N/A	NP_000684.2	P47895
	ALDH1A3	NM_001293815.2		c.204+127T>G		intron	N/A	NP_001280744.1	H0Y2X5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH1A3	ENST00000329841.10	TSL:1 MANE Select	c.204+127T>G		intron	N/A	ENSP00000332256.5	P47895
	ALDH1A3	ENST00000346623.6	TSL:1	c.204+127T>G		intron	N/A	ENSP00000343294.6	H0Y2X5
	ALDH1A3	ENST00000560555.1	TSL:1	n.264+127T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000203 AC: 1 AN: 492360 Hom.: 0 AF XY: 0.00000383 AC XY: 1 AN XY: 261356

African (AFR) AF: 0.00 AC: 0 AN: 13610

American (AMR) AF: 0.00 AC: 0 AN: 23816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15094

East Asian (EAS) AF: 0.00 AC: 0 AN: 30928

South Asian (SAS) AF: 0.00 AC: 0 AN: 49652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3504

European-Non Finnish (NFE) AF: 0.00000336 AC: 1 AN: 297896

Other (OTH) AF: 0.00 AC: 0 AN: 27458

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.23
DANN	Benign	0.36
PhyloP100		-1.3

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: rs4646656; hg19: chr15-101425703;