NM_014164.6:c.361C>T

Variant names:

• chr19-35164224-C-T
• rs535139146
• NM_014164.6:c.361C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014164.6(FXYD5):​c.361C>T​(p.Pro121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,612,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P121T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: FXYD5 NM_014164.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.35
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021525294).

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.361C>T	p.Pro121Ser	missense	Exon 6 of 9	NP_054883.3
	FXYD5	NM_001320912.2		c.361C>T	p.Pro121Ser	missense	Exon 6 of 9	NP_001307841.1	F5H4X8
	FXYD5	NM_001164605.2		c.361C>T	p.Pro121Ser	missense	Exon 6 of 9	NP_001158077.1	Q96DB9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD5	ENST00000392219.7	TSL:1 MANE Select	c.361C>T	p.Pro121Ser	missense	Exon 6 of 9	ENSP00000376053.2	Q96DB9-1
	FXYD5	ENST00000342879.7	TSL:1	c.361C>T	p.Pro121Ser	missense	Exon 5 of 8	ENSP00000344254.3	Q96DB9-1
	FXYD5	ENST00000392217.3	TSL:1	c.148C>T	p.Pro50Ser	missense	Exon 1 of 4	ENSP00000376051.3	Q96DB9-2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000521 AC: 13 AN: 249558 AF XY: 0.0000816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1460772 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 726676

African (AFR) AF: 0.0000299 AC: 1 AN: 33424

American (AMR) AF: 0.000112 AC: 5 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111550

Other (OTH) AF: 0.000116 AC: 7 AN: 60340

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152162 Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41502

American (AMR) AF: 0.000458 AC: 7 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000329 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.29
DANN	Benign	0.40
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.4
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.022
Sift	Benign	0.43	T
Sift4G	Benign	0.26	T
Polyphen		0.52	P
Vest4		0.047
MutPred		0.23		Gain of phosphorylation at P121 (P = 0.035)
MVP		0.34
MPC		0.56
ClinPred		0.046	T
GERP RS		-1.2
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.062
Mutation Taster		=97/3	polymorphism

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: rs535139146; hg19: chr19-35655127; COSMIC: COSV104654660; COSMIC: COSV104654660;