NM_001278182.2:c.1841C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278182.2(EOMES):c.1841C>G(p.Thr614Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,106 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EOMES
NM_001278182.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Publications

0 publications found

Variant links:

Genes affected

EOMES (HGNC:3372): (eomesodermin) This gene belongs to the TBR1 (T-box brain protein 1) sub-family of T-box genes that share the common DNA-binding T-box domain. The encoded protein is a transcription factor which is crucial for embryonic development of mesoderm and the central nervous system in vertebrates. The protein may also be necessary for the differentiation of effector CD8+ T cells which are involved in defense against viral infections. A similar gene disrupted in mice is shown to be essential during trophoblast development and gastrulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

EOMES Gene-Disease associations (from GenCC):

microcephaly-polymicrogyria-corpus callosum agenesis syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

EOMES links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.20343837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EOMES	NM_001278182.2 link	c.1841C>G	p.Thr614Arg	missense_variant	Exon 6 of 6	ENST00000449599.4	NP_001265111.1	O95936-4B7Z4K0
EOMES	NM_005442.4 link	c.1784C>G	p.Thr595Arg	missense_variant	Exon 6 of 6		NP_005433.2	O95936-1B7Z4K0
EOMES	NM_001278183.2 link	c.956C>G	p.Thr319Arg	missense_variant	Exon 6 of 6		NP_001265112.1	O95936-3
EOMES	XM_005265510.5 link	c.*174C>G		3_prime_UTR_variant	Exon 7 of 7		XP_005265567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EOMES	ENST00000449599.4 link	c.1841C>G	p.Thr614Arg	missense_variant	Exon 6 of 6	1	NM_001278182.2	ENSP00000388620.1	O95936-4
EOMES	ENST00000295743.8 link	c.1784C>G	p.Thr595Arg	missense_variant	Exon 6 of 6	1		ENSP00000295743.4	O95936-1
EOMES	ENST00000461503.2 link	c.956C>G	p.Thr319Arg	missense_variant	Exon 6 of 6	2		ENSP00000487112.1	O95936-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1784C>G (p.T595R) alteration is located in exon 6 (coding exon 6) of the EOMES gene. This alteration results from a C to G substitution at nucleotide position 1784, causing the threonine (T) at amino acid position 595 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Uncertain

0.44

T;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.040

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.33

N;.;.

PhyloP100

7.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

N;N;.

REVEL

Benign

0.21

Sift

Benign

0.19

T;T;.

Sift4G

Benign

0.54

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.39

MutPred

0.19

Gain of MoRF binding (P = 0.025);.;.;

MVP

0.45

MPC

0.79

ClinPred

0.39

GERP RS

3.9

Varity_R

0.13

gMVP

0.25

Mutation Taster

=70/30

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over