dbSNP rs12110: FXYD5:p.Arg176His (chr19-35169605-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014164.6(FXYD5):c.527G>A(p.Arg176His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,606,312 control chromosomes in the GnomAD database, including 523,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.83 ( 53468 hom., cov: 31)

Exomes 𝑓: 0.80 ( 470210 hom. )

Consequence

FXYD5
NM_014164.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.82

Publications

48 publications found

Variant links:

Genes affected

FXYD5 (HGNC:4029): (FXYD domain containing ion transport regulator 5) This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. Mouse FXYD5 has been termed RIC (Related to Ion Channel). FXYD2, also known as the gamma subunit of the Na,K-ATPase, regulates the properties of that enzyme. FXYD1 (phospholemman), FXYD2 (gamma), FXYD3 (MAT-8), FXYD4 (CHIF), and FXYD5 (RIC) have been shown to induce channel activity in experimental expression systems. Transmembrane topology has been established for two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. This gene product, FXYD5, is a glycoprotein that functions in the up-regulation of chemokine production, and it is involved in the reduction of cell adhesion via its ability to down-regulate E-cadherin. It also promotes metastasis, and has been linked to a variety of cancers. Alternative splicing results in multiple transcript variants. [RefSeq curation by Kathleen J. Sweadner, Ph.D., sweadner@helix.mgh.harvard.edu., Sep 2009]

FXYD5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0205597E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXYD5	NM_014164.6 link	c.527G>A	p.Arg176His	missense_variant	Exon 9 of 9	ENST00000392219.7	NP_054883.3	Q96DB9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXYD5	ENST00000392219.7 link	c.527G>A	p.Arg176His	missense_variant	Exon 9 of 9	1	NM_014164.6	ENSP00000376053.2		Q96DB9-1

Frequencies

GnomAD3 genomes

AF:

0.835

AC:

126916

AN:

152054

Hom.:

53411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.948

Gnomad AMI

AF:

0.783

Gnomad AMR

AF:

0.841

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.794

Gnomad SAS

AF:

0.872

Gnomad FIN

AF:

0.759

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.787

Gnomad OTH

AF:

0.799

GnomAD2 exomes

AF:

0.812

AC:

202037

AN:

248846

AF XY:

0.808

show subpopulations

Gnomad AFR exome

AF:

0.953

Gnomad AMR exome

AF:

0.892

Gnomad ASJ exome

AF:

0.681

Gnomad EAS exome

AF:

0.776

Gnomad FIN exome

AF:

0.762

Gnomad NFE exome

AF:

0.779

Gnomad OTH exome

AF:

0.790

GnomAD4 exome

AF:

0.803

AC:

1166949

AN:

1454140

Hom.:

470210

Cov.:

AF XY:

0.802

AC XY:

580811

AN XY:

723890

show subpopulations

African (AFR)

AF:

0.951

AC:

31745

AN:

33390

American (AMR)

AF:

0.886

AC:

39621

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

17648

AN:

26078

East Asian (EAS)

AF:

0.802

AC:

31803

AN:

39670

South Asian (SAS)

AF:

0.869

AC:

74851

AN:

86124

European-Finnish (FIN)

AF:

0.760

AC:

40547

AN:

53386

Middle Eastern (MID)

AF:

0.701

AC:

4022

AN:

5736

European-Non Finnish (NFE)

AF:

0.795

AC:

878561

AN:

1104902

Other (OTH)

AF:

0.800

AC:

48151

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

10759

21517

32276

43034

53793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20644

41288

61932

82576

103220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.835

AC:

127032

AN:

152172

Hom.:

53468

Cov.:

AF XY:

0.832

AC XY:

61894

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.948

AC:

39377

AN:

41548

American (AMR)

AF:

0.841

AC:

12861

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

2351

AN:

3468

East Asian (EAS)

AF:

0.795

AC:

4100

AN:

5160

South Asian (SAS)

AF:

0.872

AC:

4202

AN:

4820

European-Finnish (FIN)

AF:

0.759

AC:

8027

AN:

10580

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.787

AC:

53522

AN:

68006

Other (OTH)

AF:

0.797

AC:

1677

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1041

2082

3124

4165

5206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.799

Hom.:

190909

Bravo

AF:

0.845

TwinsUK

AF:

0.803

AC:

2978

ALSPAC

AF:

0.809

AC:

3117

ESP6500AA

AF:

0.946

AC:

4167

ESP6500EA

AF:

0.778

AC:

6690

ExAC

AF:

0.811

AC:

98497

Asia WGS

AF:

0.865

AC:

3012

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.9

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.0076

T;T;T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.42

.;.;.;.;T;T

MetaRNN

Benign

0.0000010

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.85

L;L;L;L;L;.

PhyloP100

-1.8

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.48

N;N;.;N;N;N

REVEL

Benign

0.011

Sift

Benign

0.64

T;T;.;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;B;B;B

Vest4

0.014

MPC

0.15

ClinPred

0.0024

GERP RS

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.012

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over