rs202006648

Variant names:

• chr12-104304014-T-C
• rs202006648
• NM_001008394.3:c.80T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-104304014-T-C
• chr12-104304014-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001008394.3(EID3):​c.80T>C​(p.Leu27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. L27R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: EID3 NM_001008394.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26847738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EID3	NM_001008394.3	c.80T>C	p.Leu27Pro	missense_variant	Exon 1 of 1	ENST00000527879.2	NP_001008395.1
TXNRD1	NM_001093771.3	c.415-7276T>C		intron_variant	Intron 4 of 16	ENST00000525566.6	NP_001087240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EID3	ENST00000527879.2	c.80T>C	p.Leu27Pro	missense_variant	Exon 1 of 1	6	NM_001008394.3	ENSP00000435619.1
TXNRD1	ENST00000525566.6	c.415-7276T>C		intron_variant	Intron 4 of 16	1	NM_001093771.3	ENSP00000434516.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000810 AC: 2 AN: 246906 AF XY: 0.00000744

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459720 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726244

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111840

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000182 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.55
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.16
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.30	B
Vest4		0.48
MutPred		0.50		Gain of loop (P = 0.0166);
MVP		0.28
MPC		0.63
ClinPred		0.14	T
GERP RS		2.6
PromoterAI		-0.0012	Neutral
Varity_R		0.19
gMVP		0.21
Mutation Taster		=98/2	polymorphism

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: rs202006648; hg19: chr12-104697792;