chr19-47780729-G-A

Variant names:

• chr19-47780729-G-A
• rs574947659
• NM_003009.4:c.34G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003009.4(SELENOW):​c.34G>A​(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,561,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A12S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SELENOW NM_003009.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79
• Publications: 0 publications found

Genes affected

SELENOW (HGNC:10752): (selenoprotein W) This gene encodes a selenoprotein containing a selenocysteine (Sec) residue, which is encoded by the UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. This protein is highly expressed in skeletal muscle, heart and brain. It belongs to the SelWTH family, which possesses a thioredoxin-like fold and a conserved CxxU (C is cysteine, U is Sec) motif, suggesting a redox function for this gene. Studies in mouse show that this selenoprotein is involved in muscle growth and differentiation, and in the protection of neurons from oxidative stress during neuronal development. A retroprocessed pseudogene of this locus has been identified on chromosome 1. [provided by RefSeq, Aug 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1724878).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003009.4. 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
	SELENOW	NM_003009.4	MANE Select	c.34G>A	p.Ala12Thr	missense	Exon 2 of 6	NP_003000.1	P63302

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SELENOW	ENST00000601048.6	TSL:1 MANE Select	c.34G>A	p.Ala12Thr	missense	Exon 2 of 6	ENSP00000473185.1	P63302
	SELENOW	ENST00000595615.1	TSL:1	c.34G>A	p.Ala12Thr	missense	Exon 2 of 5	ENSP00000470941.1	P63302
	SELENOW	ENST00000593892.5	TSL:3	c.34G>A	p.Ala12Thr	missense	Exon 2 of 6	ENSP00000471149.1	P63302

Frequencies

GnomAD3 genomes AF: 0.0000596 AC: 9 AN: 151092 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.0000743 AC: 13 AN: 174850 AF XY: 0.0000862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000769

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.000415

GnomAD4 exome AF: 0.000116 AC: 164 AN: 1410538 Hom.: 0 Cov.: 30 AF XY: 0.000115 AC XY: 80 AN XY: 696806

African (AFR) AF: 0.00 AC: 0 AN: 32244

American (AMR) AF: 0.000109 AC: 4 AN: 36788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 36958

South Asian (SAS) AF: 0.0000873 AC: 7 AN: 80176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.000136 AC: 148 AN: 1084662

Other (OTH) AF: 0.0000855 AC: 5 AN: 58498

GnomAD4 genome AF: 0.0000596 AC: 9 AN: 151092 Hom.: 0 Cov.: 28 AF XY: 0.0000407 AC XY: 3 AN XY: 73650

African (AFR) AF: 0.0000486 AC: 2 AN: 41120

American (AMR) AF: 0.00 AC: 0 AN: 15018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67904

Other (OTH) AF: 0.000483 AC: 1 AN: 2072

Alfa AF: 0.0000219 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.000110 AC: 13

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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.17	T
PhyloP100		1.8
PrimateAI	Pathogenic	0.83	D
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.12
MVP		0.75
MPC		0.072
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs574947659; hg19: chr19-48283986;