19-35169590-G-C

Variant names:

• chr19-35169590-G-C
• rs141471950
• NM_014164.6:c.512G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014164.6(FXYD5):​c.512G>C​(p.Arg171Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,459,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R171Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: FXYD5 NM_014164.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.494
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2190193).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014164.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD5	NM_014164.6	MANE Select	c.512G>C	p.Arg171Pro	missense	Exon 9 of 9	NP_054883.3
	FXYD5	NM_001164605.2		c.512G>C	p.Arg171Pro	missense	Exon 9 of 9	NP_001158077.1	Q96DB9-1
	FXYD5	NM_144779.3		c.512G>C	p.Arg171Pro	missense	Exon 9 of 9	NP_659003.1	Q96DB9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD5	ENST00000392219.7	TSL:1 MANE Select	c.512G>C	p.Arg171Pro	missense	Exon 9 of 9	ENSP00000376053.2	Q96DB9-1
	FXYD5	ENST00000342879.7	TSL:1	c.512G>C	p.Arg171Pro	missense	Exon 8 of 8	ENSP00000344254.3	Q96DB9-1
	FXYD5	ENST00000392217.3	TSL:1	c.299G>C	p.Arg100Pro	missense	Exon 4 of 4	ENSP00000376051.3	Q96DB9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459440 Hom.: 0 Cov.: 29 AF XY: 0.0000220 AC XY: 16 AN XY: 726216

African (AFR) AF: 0.0000299 AC: 1 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1109784

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.76
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.49
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Benign	0.086	T
Polyphen		0.77	P
Vest4		0.38
MutPred		0.62		Loss of MoRF binding (P = 0.0012)
MVP		0.46
MPC		0.29
ClinPred		0.21	T
GERP RS		-6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs141471950; hg19: chr19-35660493;