12-49964092-A-T

Variant names:

• chr12-49964092-A-T
• rs398123056
• NM_001651.4:c.529A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001651.4(AQP5):​c.529A>T​(p.Ile177Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AQP5 NM_001651.4 missense, splice_region
• Scores: Splicing: ADA: 0.2674
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.46
• Publications: 5 publications found

Genes affected

AQP5 (HGNC:638): (aquaporin 5) Aquaporin 5 (AQP5) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 5 plays a role in the generation of saliva, tears and pulmonary secretions. AQP0, AQP2, AQP5, and AQP6 are closely related and all map to 12q13. [provided by RefSeq, Jul 2008]

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 12-49964092-A-T is Pathogenic according to our data. Variant chr12-49964092-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 65481.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP5	NM_001651.4	c.529A>T	p.Ile177Phe	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000293599.7	NP_001642.1
AQP5	XM_005268838.3	c.529A>T	p.Ile177Phe	missense_variant, splice_region_variant	Exon 3 of 5		XP_005268895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP5	ENST00000293599.7	c.529A>T	p.Ile177Phe	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_001651.4	ENSP00000293599.5
AQP5	ENST00000553132.1	n.518A>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
AQP5-AS1	ENST00000750790.1	n.301+1591T>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Palmoplantar keratoderma, Bothnian type Pathogenic:1

Aug 08, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.96
MutPred		0.70		Loss of stability (P = 0.133);
MVP		0.98
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.86
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.020		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: rs398123056; hg19: chr12-50357875;