Genetic Variant ALDH1A3:c.204+127T>C (chr15-100885498-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000693.4(ALDH1A3):c.204+127T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 644,068 control chromosomes in the GnomAD database, including 36,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 13422 hom., cov: 32)

Exomes 𝑓: 0.27 ( 23063 hom. )

Consequence

ALDH1A3
NM_000693.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.27

Publications

4 publications found

Variant links:

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)

ALDH1A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 15-100885498-T-C is Benign according to our data. Variant chr15-100885498-T-C is described in ClinVar as Benign. ClinVar VariationId is 683870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

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>C		intron	N/A	NP_000684.2	P47895
	ALDH1A3	NM_001293815.2		c.204+127T>C		intron	N/A	NP_001280744.1	H0Y2X5

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

AF:

0.366

AC:

55599

AN:

152032

Hom.:

13381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.219

Gnomad EAS

AF:

0.681

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.245

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.330

GnomAD4 exome

AF:

0.267

AC:

131419

AN:

491918

Hom.:

23063

AF XY:

0.263

AC XY:

68770

AN XY:

261122

show subpopulations

African (AFR)

AF:

0.673

AC:

9143

AN:

13592

American (AMR)

AF:

0.328

AC:

7809

AN:

23798

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

3445

AN:

15074

East Asian (EAS)

AF:

0.709

AC:

21916

AN:

30900

South Asian (SAS)

AF:

0.251

AC:

12435

AN:

49634

European-Finnish (FIN)

AF:

0.242

AC:

7342

AN:

30366

Middle Eastern (MID)

AF:

0.220

AC:

772

AN:

3502

European-Non Finnish (NFE)

AF:

0.204

AC:

60645

AN:

297612

Other (OTH)

AF:

0.288

AC:

7912

AN:

27440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

4131

8261

12392

16522

20653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

700

1400

2100

2800

3500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.366

AC:

55703

AN:

152150

Hom.:

13422

Cov.:

AF XY:

0.367

AC XY:

27319

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.665

AC:

27565

AN:

41468

American (AMR)

AF:

0.335

AC:

5121

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

760

AN:

3470

East Asian (EAS)

AF:

0.680

AC:

3522

AN:

5178

South Asian (SAS)

AF:

0.256

AC:

1236

AN:

4832

European-Finnish (FIN)

AF:

0.245

AC:

2593

AN:

10600

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14082

AN:

67994

Other (OTH)

AF:

0.332

AC:

700

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1487

2974

4460

5947

7434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

498

996

1494

1992

2490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.249

Hom.:

9695

Bravo

AF:

0.388

Asia WGS

AF:

0.477

AC:

1656

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.28

(source)

DANN

Benign

0.22

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over