rs780523872

Variant names:

• chr3-27717347-G-A
• rs780523872
• NM_001278182.2:c.1841C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-27717347-G-A
• chr3-27717347-G-C
• chr3-27717347-G-T

Variant summary

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

The NM_001278182.2(EOMES):​c.1841C>T​(p.Thr614Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. T614R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EOMES NM_001278182.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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

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=0.22758496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EOMES	NM_001278182.2	c.1841C>T	p.Thr614Ile	missense_variant	Exon 6 of 6	ENST00000449599.4	NP_001265111.1
EOMES	NM_005442.4	c.1784C>T	p.Thr595Ile	missense_variant	Exon 6 of 6		NP_005433.2
EOMES	NM_001278183.2	c.956C>T	p.Thr319Ile	missense_variant	Exon 6 of 6		NP_001265112.1
EOMES	XM_005265510.5	c.*174C>T		3_prime_UTR_variant	Exon 7 of 7		XP_005265567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EOMES	ENST00000449599.4	c.1841C>T	p.Thr614Ile	missense_variant	Exon 6 of 6	1	NM_001278182.2	ENSP00000388620.1
EOMES	ENST00000295743.8	c.1784C>T	p.Thr595Ile	missense_variant	Exon 6 of 6	1		ENSP00000295743.4
EOMES	ENST00000461503.2	c.956C>T	p.Thr319Ile	missense_variant	Exon 6 of 6	2		ENSP00000487112.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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

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: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Benign	-0.070
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.8	L;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.12	T;T;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.045	B;.;.
Vest4		0.30
MutPred		0.27		Loss of disorder (P = 0.0241);.;.;
MVP		0.44
MPC		0.68
ClinPred		0.70	D
GERP RS		3.9
Varity_R		0.085
gMVP		0.20
Mutation Taster		=76/24	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: rs780523872; hg19: chr3-27758838;