10-43373649-C-A

Variant names:

• chr10-43373649-C-A
• rs10899795
• NM_173160.3:c.-98C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• Publications: 13 publications found

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173160.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD4	NM_173160.3	MANE Select	c.-98C>A		5_prime_UTR	Exon 3 of 9	NP_775183.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD4	ENST00000476166.6	TSL:1 MANE Select	c.-98C>A		5_prime_UTR	Exon 3 of 9	ENSP00000473361.1
	FXYD4	ENST00000616495.1	TSL:5	c.-98C>A		5_prime_UTR	Exon 2 of 8	ENSP00000483791.1
	FXYD4	ENST00000480834.5	TSL:2	n.92-821C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48658 AN: 151898 Hom.: 8702 Cov.: 32

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.: 7 AF XY: 0.274 AC XY: 94284 AN XY: 343638

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

GnomAD4 genome AF: 0.321 AC: 48723 AN: 152016 Hom.: 8722 Cov.: 32 AF XY: 0.326 AC XY: 24218 AN XY: 74314

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: 75 AN: 292

European-Non Finnish (NFE) AF: 0.226 AC: 15368 AN: 67964

Other (OTH) AF: 0.289 AC: 610 AN: 2110

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	18
DANN	Benign	0.40
PhyloP100		-0.095
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10899795; hg19: chr10-43869097; COSMIC: COSV101519294; COSMIC: COSV101519294;