19-35157462-T-G

Variant names:

• chr19-35157462-T-G
• rs1688005
• NM_014164.6:c.103T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014164.6(FXYD5):​c.103T>G​(p.Ser35Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,587,782 control chromosomes in the GnomAD database, including 70,309 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (7771 hom., cov: 31)
  • Exomes 𝑓: 0.28 (62538 hom.)
• Consequence: FXYD5 NM_014164.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28

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 (MetaRNN=1.0512871E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXYD5	NM_014164.6	c.103T>G	p.Ser35Ala	missense_variant	Exon 3 of 9	ENST00000392219.7	NP_054883.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXYD5	ENST00000392219.7	c.103T>G	p.Ser35Ala	missense_variant	Exon 3 of 9	1	NM_014164.6	ENSP00000376053.2

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45770 AN: 151778 Hom.: 7764 Cov.: 31

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.326 AC: 81737 AN: 250832 Hom.: 16140 AF XY: 0.319 AC XY: 43299 AN XY: 135588

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.823

Gnomad SAS exome AF: 0.306

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.276 AC: 396315 AN: 1435884 Hom.: 62538 Cov.: 26 AF XY: 0.276 AC XY: 197638 AN XY: 715904

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.824

Gnomad4 SAS exome AF: 0.304

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome AF: 0.302 AC: 45819 AN: 151898 Hom.: 7771 Cov.: 31 AF XY: 0.308 AC XY: 22866 AN XY: 74218

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.808

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.291

Alfa AF: 0.266 Hom.: 14245

Bravo AF: 0.308

TwinsUK AF: 0.248 AC: 921

ALSPAC AF: 0.254 AC: 979

ESP6500AA AF: 0.325 AC: 1434

ESP6500EA AF: 0.252 AC: 2165

ExAC AF: 0.321 AC: 38947

Asia WGS AF: 0.538 AC: 1869 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.245

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.030
DANN	Benign	0.53
DEOGEN2	Benign	0.016	T;T;T;T;T;T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.15	T;.;.;.;.;.;T;T
MetaRNN	Benign	0.0000011	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.20	.;.;N;N;N;N;.;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.82	N;N;N;N;.;N;.;N
REVEL	Benign	0.041
Sift	Benign	0.16	T;T;T;T;.;T;.;T
Sift4G	Benign	0.85	T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;B;B
Vest4		0.073
MPC		0.096
ClinPred		0.0055	T
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.035

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: rs1688005; hg19: chr19-35648365; COSMIC: COSV54343702; COSMIC: COSV54343702;