15-100914981-C-T

Variant names:

• chr15-100914981-C-T
• rs3803426
• ENST00000560068.2:n.1490G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000560068.2(ALDH1A3-AS1):​n.1490G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 571,442 control chromosomes in the GnomAD database, including 904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (480 hom., cov: 33)
  • Exomes 𝑓: 0.035 (424 hom.)
• Consequence: ALDH1A3-AS1 ENST00000560068.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.465
• Publications: 6 publications found

Genes affected

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

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 15-100914981-C-T is Benign according to our data. Variant chr15-100914981-C-T is described in ClinVar as Benign. ClinVar VariationId is 1287624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.*208C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000329841.10	NP_000684.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.*208C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes AF: 0.0614 AC: 9348 AN: 152182 Hom.: 480 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0385

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.0492

Gnomad FIN AF: 0.0523

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0559

GnomAD4 exome AF: 0.0349 AC: 14647 AN: 419142 Hom.: 424 Cov.: 4 AF XY: 0.0350 AC XY: 7710 AN XY: 219984

African (AFR) AF: 0.141 AC: 1680 AN: 11932

American (AMR) AF: 0.0278 AC: 492 AN: 17694

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 707 AN: 12658

East Asian (EAS) AF: 0.0743 AC: 2171 AN: 29220

South Asian (SAS) AF: 0.0459 AC: 1936 AN: 42168

European-Finnish (FIN) AF: 0.0429 AC: 1145 AN: 26674

Middle Eastern (MID) AF: 0.0517 AC: 94 AN: 1818

European-Non Finnish (NFE) AF: 0.0215 AC: 5438 AN: 252938

Other (OTH) AF: 0.0409 AC: 984 AN: 24040

GnomAD4 genome AF: 0.0615 AC: 9361 AN: 152300 Hom.: 480 Cov.: 33 AF XY: 0.0630 AC XY: 4695 AN XY: 74476

African (AFR) AF: 0.142 AC: 5895 AN: 41542

American (AMR) AF: 0.0384 AC: 587 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3470

East Asian (EAS) AF: 0.0671 AC: 348 AN: 5190

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4830

European-Finnish (FIN) AF: 0.0523 AC: 555 AN: 10612

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0206 AC: 1401 AN: 68038

Other (OTH) AF: 0.0558 AC: 118 AN: 2116

Alfa AF: 0.0333 Hom.: 741

Bravo AF: 0.0634

Asia WGS AF: 0.0530 AC: 186 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.6
DANN	Benign	0.82
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs3803426; hg19: chr15-101455186;