rs4646669

Variant names:

• chr15-100896102-C-T
• rs4646669
• NM_000693.4:c.780+56C>T

Variant summary

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

The NM_000693.4(ALDH1A3):​c.780+56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,347,706 control chromosomes in the GnomAD database, including 21,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2395 hom., cov: 32)
  • Exomes 𝑓: 0.17 (18656 hom.)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.32
• 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-AS1 (HGNC:55416): (ALDH1A3 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-100896102-C-T is Benign according to our data. Variant chr15-100896102-C-T is described in ClinVar as Benign. ClinVar VariationId is 677157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH1A3	NM_000693.4	c.780+56C>T		intron_variant	Intron 7 of 12	ENST00000329841.10	NP_000684.2
ALDH1A3	NM_001293815.2	c.459+56C>T		intron_variant	Intron 4 of 9		NP_001280744.1
ALDH1A3-AS1	NR_135827.1	n.481-36G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH1A3	ENST00000329841.10	c.780+56C>T		intron_variant	Intron 7 of 12	1	NM_000693.4	ENSP00000332256.5

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25458 AN: 151996 Hom.: 2392 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0897

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.154

GnomAD4 exome AF: 0.167 AC: 200114 AN: 1195590 Hom.: 18656 Cov.: 16 AF XY: 0.166 AC XY: 99561 AN XY: 598250

African (AFR) AF: 0.131 AC: 3621 AN: 27616

American (AMR) AF: 0.252 AC: 9136 AN: 36298

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3289 AN: 23842

East Asian (EAS) AF: 0.409 AC: 14325 AN: 35060

South Asian (SAS) AF: 0.126 AC: 9486 AN: 75562

European-Finnish (FIN) AF: 0.159 AC: 7954 AN: 49982

Middle Eastern (MID) AF: 0.122 AC: 643 AN: 5256

European-Non Finnish (NFE) AF: 0.160 AC: 142754 AN: 890632

Other (OTH) AF: 0.173 AC: 8906 AN: 51342

GnomAD4 genome AF: 0.167 AC: 25468 AN: 152116 Hom.: 2395 Cov.: 32 AF XY: 0.169 AC XY: 12542 AN XY: 74352

African (AFR) AF: 0.135 AC: 5614 AN: 41500

American (AMR) AF: 0.222 AC: 3390 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 455 AN: 3470

East Asian (EAS) AF: 0.415 AC: 2148 AN: 5174

South Asian (SAS) AF: 0.119 AC: 573 AN: 4812

European-Finnish (FIN) AF: 0.156 AC: 1648 AN: 10582

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.165 AC: 11224 AN: 67994

Other (OTH) AF: 0.154 AC: 325 AN: 2110

Alfa AF: 0.163 Hom.: 3619

Bravo AF: 0.174

Asia WGS AF: 0.268 AC: 932 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.11
DANN	Benign	0.59
PhyloP100		-2.3
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: rs4646669; hg19: chr15-101436307; COSMIC: COSV60901215; COSMIC: COSV60901215;