7-30912049-A-G

Position:

• chr7-30912049-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_198098.4(AQP1):​c.140A>G​(p.Gln47Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,392 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (4 hom.)
• Consequence: AQP1 NM_198098.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

Genes affected

AQP1 (HGNC:633): (aquaporin 1 (Colton blood group)) This gene encodes a small integral membrane protein with six bilayer spanning domains that functions as a water channel protein. This protein permits passive transport of water along an osmotic gradient. This gene is a possible candidate for disorders involving imbalance in ocular fluid movement. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 4 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP1	NM_198098.4	c.140A>G	p.Gln47Arg	missense_variant	1/4	ENST00000311813.11	NP_932766.1
AQP1	NM_001329872.2	c.140A>G	p.Gln47Arg	missense_variant	1/5		NP_001316801.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP1	ENST00000311813.11	c.140A>G	p.Gln47Arg	missense_variant	1/4	1	NM_198098.4	ENSP00000311165	P1
AQP1	ENST00000652696.1	c.140A>G	p.Gln47Arg	missense_variant	1/5			ENSP00000498672	P1
AQP1	ENST00000441328.7			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251086 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135858

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000146 AC: 214 AN: 1461150 Hom.: 4 Cov.: 32 AF XY: 0.000172 AC XY: 125 AN XY: 726900

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000276 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects AQP1 function (PMID: 20492605). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AQP1 protein function. This variant has not been reported in the literature in individuals affected with AQP1-related conditions. This variant is present in population databases (rs377506522, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 47 of the AQP1 protein (p.Gln47Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.99	D;D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.76
Sift	Benign	0.13	T
Sift4G	Benign	0.28	T
Polyphen		0.99	D
Vest4		0.85
MVP		0.90
MPC		1.3
ClinPred		0.37	T
GERP RS		4.5
Varity_R		0.52
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs377506522; hg19: chr7-30951664;