11-77590254-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173039.3(AQP11):c.262G>T(p.Val88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,601,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: AQP11 NM_173039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

Genes affected

AQP11 (HGNC:19940): (aquaporin 11) Enables glycerol channel activity and water channel activity. Involved in several processes, including glycerol transport; hydrogen peroxide transmembrane transport; and protein homooligomerization. Located in cell surface; endoplasmic reticulum; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CLNS1A (HGNC:2080): (chloride nucleotide-sensitive channel 1A) This gene encodes a protein that functions in multiple regulatory pathways. The encoded protein complexes with numerous cytosolic proteins and performs diverse functions including regulation of small nuclear ribonucleoprotein biosynthesis, platelet activation and cytoskeletal organization. The protein is also found associated with the plasma membrane where it functions as a chloride current regulator. Pseudogenes of this gene are found on chromosomes 1, 4 and 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3812795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP11	NM_173039.3	c.262G>T	p.Val88Leu	missense_variant	1/3	ENST00000313578.4
AQP11	NM_001363477.2	c.262G>T	p.Val88Leu	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP11	ENST00000313578.4	c.262G>T	p.Val88Leu	missense_variant	1/3	1	NM_173039.3	P1
AQP11	ENST00000528638.1	n.291-275G>T		intron_variant, non_coding_transcript_variant		1
CLNS1A	ENST00000526761.5	c.*156-4795C>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000577 AC: 14 AN: 242540 Hom.: 0 AF XY: 0.0000535 AC XY: 7 AN XY: 130774

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000117 AC: 170 AN: 1448960 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 82 AN XY: 719242

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000765

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74366

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.262G>T (p.V88L) alteration is located in exon 1 (coding exon 1) of the AQP11 gene. This alteration results from a G to T substitution at nucleotide position 262, causing the valine (V) at amino acid position 88 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.061
Sift	Benign	0.36	T
Sift4G	Benign	0.57	T
Polyphen		0.77	P
Vest4		0.075
MutPred		0.65		Loss of helix (P = 0.2662);
MVP		0.73
MPC		1.4
ClinPred		0.17	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs557986456; hg19: chr11-77301299;