Genetic Variant FXYD4:c.-98C>A (chr10-43373649-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_ModerateBA1

The NM_173160.3(FXYD4):c.-98C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 786,940 control chromosomes in the GnomAD database, including 33,873 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 8722 hom., cov: 32)

Exomes 𝑓: 0.27 ( 25151 hom. )

Consequence

FXYD4
NM_173160.3 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0950

Publications

13 publications found

Variant links:

Genes affected

FXYD4 (HGNC:4028): (FXYD domain containing ion transport regulator 4) 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. FXYD4, originally named CHIF for channel-inducing factor, has been shown to modulate the properties of the Na,K-ATPase, as has FXYD2, also known as the gamma subunit of the Na,K-ATPase, and FXYD7. Transmembrane topology has been established for FXYD4 and two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. Alternatively spliced transcript variants encoding the same protein have been found.[provided by RefSeq, May 2010]

FXYD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXYD4	NM_173160.3 link	c.-98C>A		5_prime_UTR_variant	Exon 3 of 9	ENST00000476166.6	NP_775183.1	P59646

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FXYD4	ENST00000476166.6 link	c.-98C>A	5_prime_UTR_variant	Exon 3 of 9	1	NM_173160.3	ENSP00000473361.1	P59646
FXYD4	ENST00000616495.1 link	c.-98C>A	5_prime_UTR_variant	Exon 2 of 8	5		ENSP00000483791.1	P59646
FXYD4	ENST00000480834.5 link	n.92-821C>A	intron_variant	Intron 2 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48658

AN:

151898

Hom.:

8702

Cov.:

show subpopulations

Gnomad AFR

AF:

0.486

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.339

Gnomad EAS

AF:

0.391

Gnomad SAS

AF:

0.357

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.226

Gnomad OTH

AF:

0.290

GnomAD4 exome

AF:

0.271

AC:

172125

AN:

634924

Hom.:

25151

Cov.:

AF XY:

0.274

AC XY:

94284

AN XY:

343638

show subpopulations

African (AFR)

AF:

0.491

AC:

8837

AN:

17998

American (AMR)

AF:

0.272

AC:

11780

AN:

43380

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

6751

AN:

20778

East Asian (EAS)

AF:

0.381

AC:

13673

AN:

35856

South Asian (SAS)

AF:

0.366

AC:

25571

AN:

69884

European-Finnish (FIN)

AF:

0.276

AC:

12424

AN:

45026

Middle Eastern (MID)

AF:

0.294

AC:

1208

AN:

4104

European-Non Finnish (NFE)

AF:

0.227

AC:

82608

AN:

364652

Other (OTH)

AF:

0.279

AC:

9273

AN:

33246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

6402

12805

19207

25610

32012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.321

AC:

48723

AN:

152016

Hom.:

8722

Cov.:

AF XY:

0.326

AC XY:

24218

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.486

AC:

20152

AN:

41446

American (AMR)

AF:

0.282

AC:

4312

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.339

AC:

1175

AN:

3470

East Asian (EAS)

AF:

0.392

AC:

2022

AN:

5152

South Asian (SAS)

AF:

0.356

AC:

1718

AN:

4824

European-Finnish (FIN)

AF:

0.291

AC:

3082

AN:

10574

Middle Eastern (MID)

AF:

0.257

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.226

AC:

15368

AN:

67964

Other (OTH)

AF:

0.289

AC:

610

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1617

3233

4850

6466

8083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.259

Hom.:

15594

Bravo

AF:

0.326

Asia WGS

AF:

0.388

AC:

1346

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.40

PhyloP100

-0.095

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 2

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

Publications

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chr10-43373649-C-A

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