15-58175767-A-C

Variant names:

• chr15-58175767-A-C
• rs1618930
• NM_020980.5:c.495+731A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020980.5(AQP9):​c.495+731A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 152,146 control chromosomes in the GnomAD database, including 16,546 homozygotes. 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: 𝑓 0.44 (16546 hom., cov: 33)
• Consequence: AQP9 NM_020980.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870
• Publications: 6 publications found

Genes affected

AQP9 (HGNC:643): (aquaporin 9) The aquaporins are a family of water-selective membrane channels. This gene encodes a member of a subset of aquaporins called the aquaglyceroporins. This protein allows passage of a broad range of noncharged solutes and also stimulates urea transport and osmotic water permeability. This protein may also facilitate the uptake of glycerol in hepatic tissue . The encoded protein may also play a role in specialized leukocyte functions such as immunological response and bactericidal activity. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ALDH1A2 (HGNC:15472): (aldehyde dehydrogenase 1 family member A2) This protein belongs to the aldehyde dehydrogenase family of proteins. The product of this gene is an enzyme that catalyzes the synthesis of retinoic acid (RA) from retinaldehyde. Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that functions in developing and adult tissues. The studies of a similar mouse gene suggest that this enzyme and the cytochrome CYP26A1, concurrently establish local embryonic retinoic acid levels which facilitate posterior organ development and prevent spina bifida. Four transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2011]

ALDH1A2 Gene-Disease associations (from GenCC):

• diaphragmatic hernia 4, with cardiovascular defects

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020980.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP9	NM_020980.5	MANE Select	c.495+731A>C		intron	N/A	NP_066190.2
	AQP9	NM_001320636.1		c.300+731A>C		intron	N/A	NP_001307565.1
	AQP9	NM_001320635.2		c.495+731A>C		intron	N/A	NP_001307564.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP9	ENST00000219919.9	TSL:1 MANE Select	c.495+731A>C		intron	N/A	ENSP00000219919.4
	ALDH1A2	ENST00000558231.5	TSL:2	c.30+103407T>G		intron	N/A	ENSP00000453600.1
	AQP9	ENST00000558772.5	TSL:2	c.300+731A>C		intron	N/A	ENSP00000452673.1

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66992 AN: 152028 Hom.: 16535 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.479

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.441 AC: 67025 AN: 152146 Hom.: 16546 Cov.: 33 AF XY: 0.445 AC XY: 33097 AN XY: 74376

African (AFR) AF: 0.212 AC: 8788 AN: 41534

American (AMR) AF: 0.593 AC: 9055 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2164 AN: 3468

East Asian (EAS) AF: 0.607 AC: 3141 AN: 5172

South Asian (SAS) AF: 0.553 AC: 2670 AN: 4828

European-Finnish (FIN) AF: 0.479 AC: 5066 AN: 10574

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34596 AN: 67982

Other (OTH) AF: 0.483 AC: 1020 AN: 2112

Alfa AF: 0.503 Hom.: 33595

Bravo AF: 0.439

Asia WGS AF: 0.542 AC: 1885 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.68
PhyloP100		-0.087
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1618930; hg19: chr15-58467966;