rs12110

Variant names:

• chr19-35169605-G-A
• rs12110
• NM_014164.6:c.527G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-35169605-G-A
• chr19-35169605-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014164.6(FXYD5):​c.527G>A​(p.Arg176His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,606,312 control chromosomes in the GnomAD database, including 523,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R176L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.83 (53468 hom., cov: 31)
  • Exomes 𝑓: 0.80 (470210 hom.)
• Consequence: FXYD5 NM_014164.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 48 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0205597E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

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.527G>A	p.Arg176His	missense	Exon 9 of 9	NP_054883.3
	FXYD5	NM_001164605.2		c.527G>A	p.Arg176His	missense	Exon 9 of 9	NP_001158077.1	Q96DB9-1
	FXYD5	NM_144779.3		c.527G>A	p.Arg176His	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.527G>A	p.Arg176His	missense	Exon 9 of 9	ENSP00000376053.2	Q96DB9-1
	FXYD5	ENST00000342879.7	TSL:1	c.527G>A	p.Arg176His	missense	Exon 8 of 8	ENSP00000344254.3	Q96DB9-1
	FXYD5	ENST00000392217.3	TSL:1	c.314G>A	p.Arg105His	missense	Exon 4 of 4	ENSP00000376051.3	Q96DB9-2

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126916 AN: 152054 Hom.: 53411 Cov.: 31

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.787

Gnomad OTH AF: 0.799

GnomAD2 exomes AF: 0.812 AC: 202037 AN: 248846 AF XY: 0.808

Gnomad AFR exome AF: 0.953

Gnomad AMR exome AF: 0.892

Gnomad ASJ exome AF: 0.681

Gnomad EAS exome AF: 0.776

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 0.790

GnomAD4 exome AF: 0.803 AC: 1166949 AN: 1454140 Hom.: 470210 Cov.: 34 AF XY: 0.802 AC XY: 580811 AN XY: 723890

African (AFR) AF: 0.951 AC: 31745 AN: 33390

American (AMR) AF: 0.886 AC: 39621 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 17648 AN: 26078

East Asian (EAS) AF: 0.802 AC: 31803 AN: 39670

South Asian (SAS) AF: 0.869 AC: 74851 AN: 86124

European-Finnish (FIN) AF: 0.760 AC: 40547 AN: 53386

Middle Eastern (MID) AF: 0.701 AC: 4022 AN: 5736

European-Non Finnish (NFE) AF: 0.795 AC: 878561 AN: 1104902

Other (OTH) AF: 0.800 AC: 48151 AN: 60152

GnomAD4 genome AF: 0.835 AC: 127032 AN: 152172 Hom.: 53468 Cov.: 31 AF XY: 0.832 AC XY: 61894 AN XY: 74388

African (AFR) AF: 0.948 AC: 39377 AN: 41548

American (AMR) AF: 0.841 AC: 12861 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2351 AN: 3468

East Asian (EAS) AF: 0.795 AC: 4100 AN: 5160

South Asian (SAS) AF: 0.872 AC: 4202 AN: 4820

European-Finnish (FIN) AF: 0.759 AC: 8027 AN: 10580

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.787 AC: 53522 AN: 68006

Other (OTH) AF: 0.797 AC: 1677 AN: 2104

Alfa AF: 0.799 Hom.: 190909

Bravo AF: 0.845

TwinsUK AF: 0.803 AC: 2978

ALSPAC AF: 0.809 AC: 3117

ESP6500AA AF: 0.946 AC: 4167

ESP6500EA AF: 0.778 AC: 6690

ExAC AF: 0.811 AC: 98497

Asia WGS AF: 0.865 AC: 3012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.9
DANN	Benign	0.58
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.85	L
PhyloP100		-1.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.011
Sift	Benign	0.64	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.014
MPC		0.15
ClinPred		0.0024	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.012
Mutation Taster		=100/0	polymorphism (auto)

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: rs12110; hg19: chr19-35660508; COSMIC: COSV100732736; COSMIC: COSV100732736;