11-117840367-C-A

Variant names:

• chr11-117840367-C-A
• rs2056310039
• NM_022003.4:c.211G>T

Variant summary

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

The NM_022003.4(FXYD6):​c.211G>T​(p.Ala71Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FXYD6 NM_022003.4 missense, splice_region
• Scores: Splicing: ADA: 0.1755
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53
• Publications: 0 publications found

Genes affected

FXYD6 (HGNC:4030): (FXYD domain containing ion transport regulator 6) This gene encodes a member of the FXYD family of transmembrane proteins. This particular protein encodes phosphohippolin, which likely affects the activity of Na,K-ATPase. Multiple alternatively spliced transcript variants encoding the same protein have been described. Related pseudogenes have been identified on chromosomes 10 and X. Read-through transcripts have been observed between this locus and the downstream sodium/potassium-transporting ATPase subunit gamma (FXYD2, GeneID 486) locus.[provided by RefSeq, Feb 2011]

FXYD6-FXYD2 (HGNC:39978): (FXYD6-FXYD2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring FXYD domain-containing ion transport regulator 6 (GeneID 53826) and sodium/potassium-transporting ATPase subunit gamma (GeneID 486) genes on chromosome 11. One read-through transcript produces a fusion protein that shares sequence identity with each individual gene product, while another read-through transcript encodes a protein that has a distinct C-terminus and only shares sequence identity with the upstream locus (GeneID 53826). [provided by RefSeq, Aug 2011]

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=0.24388486).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022003.4. 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
	FXYD6	NM_022003.4	MANE Select	c.211G>T	p.Ala71Ser	missense splice_region	Exon 6 of 8	NP_071286.1	Q9H0Q3-1
	FXYD6-FXYD2	NM_001243598.4		c.174G>T	p.Arg58Ser	missense splice_region	Exon 5 of 10	NP_001230527.1	A0A0A6YYL5
	FXYD6	NM_001164831.3		c.211G>T	p.Ala71Ser	missense splice_region	Exon 6 of 8	NP_001158303.1	Q9H0Q3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXYD6	ENST00000526014.6	TSL:1 MANE Select	c.211G>T	p.Ala71Ser	missense splice_region	Exon 6 of 8	ENSP00000433312.1	Q9H0Q3-1
	FXYD6	ENST00000260282.8	TSL:1	c.211G>T	p.Ala71Ser	missense splice_region	Exon 8 of 10	ENSP00000260282.4	Q9H0Q3-1
	FXYD6	ENST00000539526.5	TSL:1	c.211G>T	p.Ala71Ser	missense splice_region	Exon 7 of 9	ENSP00000442756.1	Q9H0Q3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

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	0.090
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.097	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.95	T
PhyloP100		4.5
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.038
Sift	Benign	0.44	T
Sift4G	Benign	0.70	T
Polyphen		0.028	B
Vest4		0.28
MutPred		0.32		Gain of phosphorylation at A71 (P = 0.0364)
MVP		0.56
MPC		0.44
ClinPred		0.35	T
GERP RS		5.4
Varity_R		0.076
gMVP		0.42
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.010		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: rs2056310039; hg19: chr11-117711082;