15-58162999-T-C

Variant names:

• chr15-58162999-T-C
• rs10518966
• NM_020980.5:c.112-3674T>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.112-3674T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,056 control chromosomes in the GnomAD database, including 17,415 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 0.45 (17415 hom., cov: 32)
• Consequence: AQP9 NM_020980.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.261
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP9	NM_020980.5	c.112-3674T>C		intron_variant	Intron 1 of 5	ENST00000219919.9	NP_066190.2
AQP9	NM_001320636.1	c.-84-3674T>C		intron_variant	Intron 1 of 5		NP_001307565.1
AQP9	NM_001320635.2	c.112-3674T>C		intron_variant	Intron 1 of 4		NP_001307564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP9	ENST00000219919.9	c.112-3674T>C		intron_variant	Intron 1 of 5	1	NM_020980.5	ENSP00000219919.4

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68878 AN: 151936 Hom.: 17409 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.489

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

GnomAD4 genome AF: 0.453 AC: 68902 AN: 152056 Hom.: 17415 Cov.: 32 AF XY: 0.456 AC XY: 33892 AN XY: 74316

African (AFR) AF: 0.217 AC: 8982 AN: 41476

American (AMR) AF: 0.609 AC: 9296 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2160 AN: 3470

East Asian (EAS) AF: 0.585 AC: 3022 AN: 5166

South Asian (SAS) AF: 0.543 AC: 2620 AN: 4828

European-Finnish (FIN) AF: 0.475 AC: 5016 AN: 10564

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.530 AC: 36054 AN: 67968

Other (OTH) AF: 0.489 AC: 1035 AN: 2116

Alfa AF: 0.510 Hom.: 68987

Bravo AF: 0.454

Asia WGS AF: 0.533 AC: 1852 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.79
DANN	Benign	0.76
PhyloP100		-0.26
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: rs10518966; hg19: chr15-58455198;