chr19-35157493-G-C

Variant names:

• chr19-35157493-G-C
• NM_014164.6:c.134G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014164.6(FXYD5):​c.134G>C​(p.Arg45Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 1,377,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: FXYD5 NM_014164.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022924274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXYD5	NM_014164.6	c.134G>C	p.Arg45Pro	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.134G>C	p.Arg45Pro	missense_variant	Exon 3 of 9	1	NM_014164.6	ENSP00000376053.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000363 AC: 5 AN: 1377676 Hom.: 0 Cov.: 21 AF XY: 0.00000580 AC XY: 4 AN XY: 690068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000593

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.68
DANN	Benign	0.60
DEOGEN2	Benign	0.0033	T;T;T;T;T;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.42	T;.;.;.;.;.;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.6	.;.;N;N;N;N;.;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	3.5	N;N;N;N;.;N;.;N
REVEL	Benign	0.048
Sift	Benign	0.27	T;T;T;T;.;T;.;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;B;B
Vest4		0.091
MutPred		0.33		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.35
MPC		0.17
ClinPred		0.11	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.047

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-35648396;