rs4646660

Variant names:

• chr15-100887793-A-C
• rs4646660
• NM_000693.4:c.345+81A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-100887793-A-C
• chr15-100887793-A-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.345+81A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,468,906 control chromosomes in the GnomAD database, including 2,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (1149 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1154 hom.)
• Consequence: ALDH1A3 NM_000693.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-100887793-A-C is Benign according to our data. Variant chr15-100887793-A-C is described in ClinVar as Benign. ClinVar VariationId is 1252718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 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.345+81A>C		intron	N/A	NP_000684.2	P47895
	ALDH1A3	NM_001293815.2		c.345+81A>C		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.345+81A>C		intron	N/A	ENSP00000332256.5	P47895
	ALDH1A3	ENST00000346623.6	TSL:1	c.345+81A>C		intron	N/A	ENSP00000343294.6	H0Y2X5
	ALDH1A3	ENST00000560555.1	TSL:1	n.405+81A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12095 AN: 152166 Hom.: 1146 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0648

Gnomad SAS AF: 0.0507

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.00971

Gnomad OTH AF: 0.0761

GnomAD4 exome AF: 0.0190 AC: 24999 AN: 1316622 Hom.: 1154 AF XY: 0.0191 AC XY: 12310 AN XY: 643384

African (AFR) AF: 0.238 AC: 6947 AN: 29142

American (AMR) AF: 0.0221 AC: 598 AN: 27120

Ashkenazi Jewish (ASJ) AF: 0.00860 AC: 168 AN: 19536

East Asian (EAS) AF: 0.0685 AC: 2478 AN: 36172

South Asian (SAS) AF: 0.0449 AC: 2953 AN: 65726

European-Finnish (FIN) AF: 0.0419 AC: 1845 AN: 44072

Middle Eastern (MID) AF: 0.0329 AC: 128 AN: 3890

European-Non Finnish (NFE) AF: 0.00797 AC: 8266 AN: 1036684

Other (OTH) AF: 0.0298 AC: 1616 AN: 54280

GnomAD4 genome AF: 0.0795 AC: 12114 AN: 152284 Hom.: 1149 Cov.: 32 AF XY: 0.0803 AC XY: 5983 AN XY: 74464

African (AFR) AF: 0.232 AC: 9653 AN: 41534

American (AMR) AF: 0.0333 AC: 510 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.0644 AC: 333 AN: 5174

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4828

European-Finnish (FIN) AF: 0.0488 AC: 518 AN: 10620

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.00972 AC: 661 AN: 68036

Other (OTH) AF: 0.0758 AC: 160 AN: 2112

Alfa AF: 0.0408 Hom.: 961

Bravo AF: 0.0849

Asia WGS AF: 0.0560 AC: 197 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.70
DANN	Benign	0.42
PhyloP100		0.35
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: rs4646660; hg19: chr15-101427998;