12-104304478-C-G

Variant names:

• chr12-104304478-C-G
• rs1456139880
• NM_001008394.3:c.544C>G

Variant summary

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

The NM_001008394.3(EID3):​c.544C>G​(p.Pro182Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,704 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. 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. P182S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EID3 NM_001008394.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 0 publications found

Genes affected

EID3 (HGNC:32961): (EP300 interacting inhibitor of differentiation 3) Predicted to be involved in DNA repair. Located in nucleolus and nucleoplasm. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

TXNRD1 (HGNC:12437): (thioredoxin reductase 1) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes an ubiquitously expressed, cytosolic form of TrxR, which functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by 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, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternative splicing, primarily at the 5' end, results in transcript variants encoding same or different isoforms, including a glutaredoxin-containing isoform that is predominantly expressed in testis. [provided by RefSeq, May 2017]

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=0.113554865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008394.3. 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
	EID3	NM_001008394.3	MANE Select	c.544C>G	p.Pro182Ala	missense	Exon 1 of 1	NP_001008395.1	Q8N140
	TXNRD1	NM_001093771.3	MANE Select	c.415-6812C>G		intron	N/A	NP_001087240.1	Q16881-1
	TXNRD1	NM_003330.4		c.121-6812C>G		intron	N/A	NP_003321.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EID3	ENST00000527879.2	TSL:6 MANE Select	c.544C>G	p.Pro182Ala	missense	Exon 1 of 1	ENSP00000435619.1	Q8N140
	TXNRD1	ENST00000525566.6	TSL:1 MANE Select	c.415-6812C>G		intron	N/A	ENSP00000434516.1	Q16881-1
	TXNRD1	ENST00000526691.5	TSL:1	c.121-6812C>G		intron	N/A	ENSP00000435929.1	Q16881-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461704 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 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: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111868

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.5
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Uncertain	0.057	T
Polyphen		0.097	B
Vest4		0.13
MutPred		0.55		Loss of glycosylation at P182 (P = 0.0133)
MVP		0.29
MPC		0.32
ClinPred		0.24	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.16
Mutation Taster		=89/11	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: rs1456139880; hg19: chr12-104698256;