rs74668961

Variant names:

• chr9-33386467-A-G
• rs74668961
• NM_001170.3:c.343T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM2 PP3 BP4_Strong BP6_Moderate

The NM_001170.3(AQP7):​c.343T>C​(p.Tyr115His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,748 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 Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AQP7 NM_001170.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.07
• Publications: 23 publications found

Genes affected

AQP7 (HGNC:640): (aquaporin 7) This gene encodes a member of the aquaporin family of water-selective membrane channels. The encoded protein localizes to the plasma membrane and allows movement of water, glycerol and urea across cell membranes. This gene is highly expressed in the adipose tissue where the encoded protein facilitates efflux of glycerol. In the proximal straight tubules of kidney, the encoded protein is localized to the apical membrane and prevents excretion of glycerol into urine. The encoded protein is present in spermatids, as well as in the testicular and epididymal spermatozoa suggesting an important role in late spermatogenesis. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. This gene is located adjacent to a related aquaporin gene on chromosome 9. Multiple pseudogenes of this gene have been identified. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011967391).
• BP6: Variant 9-33386467-A-G is Benign according to our data. Variant chr9-33386467-A-G is described in ClinVar as Benign. ClinVar VariationId is 402389.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP7	NM_001170.3	c.343T>C	p.Tyr115His	missense_variant	Exon 5 of 8	ENST00000297988.6	NP_001161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP7	ENST00000297988.6	c.343T>C	p.Tyr115His	missense_variant	Exon 5 of 8	1	NM_001170.3	ENSP00000297988.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00729 AC: 1159 AN: 159024 AF XY: 0.00589

Gnomad AFR exome AF: 0.00588

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.00489

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459748 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725970

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111200

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 32

Alfa AF: 0.153 Hom.: 0

ExAC AF: 0.0475 AC: 5770

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;D;.;.;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;T;T;T;T;T;T
MetaRNN	Benign	0.012	T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
PhyloP100		9.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.026	D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;D;D
Polyphen		0.60, 0.81, 0.93, 0.73	.;P;P;.;P;P;.
Vest4		0.34
MPC		0.40
ClinPred		0.060	T
GERP RS		4.4
Varity_R		0.84
Mutation Taster		=39/61	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74668961; hg19: chr9-33386465; COSMIC: COSV53003174; COSMIC: COSV53003174;