rs2285515

Variant names:

• chr19-35169547-T-C
• rs2285515
• NM_014164.6:c.488-19T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014164.6(FXYD5):​c.488-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,571,758 control chromosomes in the GnomAD database, including 107,191 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 0.35 (9612 hom., cov: 31)
  • Exomes 𝑓: 0.36 (97579 hom.)
• Consequence: FXYD5 NM_014164.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 27 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXYD5	NM_014164.6	c.488-19T>C		intron_variant	Intron 8 of 8	ENST00000392219.7	NP_054883.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXYD5	ENST00000392219.7	c.488-19T>C		intron_variant	Intron 8 of 8	1	NM_014164.6	ENSP00000376053.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53016 AN: 151836 Hom.: 9609 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.332 AC: 82657 AN: 248684 AF XY: 0.337

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.334

GnomAD4 exome AF: 0.364 AC: 516811 AN: 1419804 Hom.: 97579 Cov.: 27 AF XY: 0.364 AC XY: 257600 AN XY: 708580

African (AFR) AF: 0.329 AC: 10763 AN: 32696

American (AMR) AF: 0.260 AC: 11598 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 7240 AN: 25932

East Asian (EAS) AF: 0.110 AC: 4357 AN: 39602

South Asian (SAS) AF: 0.327 AC: 27993 AN: 85496

European-Finnish (FIN) AF: 0.386 AC: 20568 AN: 53344

Middle Eastern (MID) AF: 0.310 AC: 1769 AN: 5704

European-Non Finnish (NFE) AF: 0.384 AC: 412228 AN: 1073378

Other (OTH) AF: 0.344 AC: 20295 AN: 58986

GnomAD4 genome AF: 0.349 AC: 53036 AN: 151954 Hom.: 9612 Cov.: 31 AF XY: 0.346 AC XY: 25718 AN XY: 74298

African (AFR) AF: 0.332 AC: 13740 AN: 41426

American (AMR) AF: 0.310 AC: 4732 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 974 AN: 3472

East Asian (EAS) AF: 0.130 AC: 672 AN: 5164

South Asian (SAS) AF: 0.321 AC: 1544 AN: 4806

European-Finnish (FIN) AF: 0.397 AC: 4195 AN: 10558

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26095 AN: 67930

Other (OTH) AF: 0.323 AC: 681 AN: 2106

Alfa AF: 0.367 Hom.: 17471

Bravo AF: 0.341

Asia WGS AF: 0.204 AC: 710 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.4
DANN	Benign	0.60
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2285515; hg19: chr19-35660450; COSMIC: COSV61568502; COSMIC: COSV61568502;