chr19-35169547-T-C

Position:

• chr19-35169547-T-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
FXYD5	NM_014164.6	c.488-19T>C		intron_variant		ENST00000392219.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXYD5	ENST00000392219.7	c.488-19T>C		intron_variant		1	NM_014164.6	P2

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

GnomAD3 exomes AF: 0.332 AC: 82657 AN: 248684 Hom.: 14603 AF XY: 0.337 AC XY: 45310 AN XY: 134600

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 SAS exome AF: 0.328

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

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.260

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.384

Gnomad4 OTH exome AF: 0.344

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

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.384

Gnomad4 OTH AF: 0.323

Alfa AF: 0.369 Hom.: 13935

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

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

LitVar

Other links and lift over

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