NM_001278182.2:c.1967C>A

Variant names:

• chr3-27717221-G-T
• rs1479706198
• NM_001278182.2:c.1967C>A

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.1967C>A​(p.Thr656Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T656I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EOMES NM_001278182.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• 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=0.15245104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EOMES	NM_001278182.2	c.1967C>A	p.Thr656Asn	missense_variant	Exon 6 of 6	ENST00000449599.4	NP_001265111.1
EOMES	NM_005442.4	c.1910C>A	p.Thr637Asn	missense_variant	Exon 6 of 6		NP_005433.2
EOMES	NM_001278183.2	c.1082C>A	p.Thr361Asn	missense_variant	Exon 6 of 6		NP_001265112.1
EOMES	XM_005265510.5	c.*300C>A		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.1967C>A	p.Thr656Asn	missense_variant	Exon 6 of 6	1	NM_001278182.2	ENSP00000388620.1
EOMES	ENST00000295743.8	c.1910C>A	p.Thr637Asn	missense_variant	Exon 6 of 6	1		ENSP00000295743.4
EOMES	ENST00000461503.2	c.1082C>A	p.Thr361Asn	missense_variant	Exon 6 of 6	2		ENSP00000487112.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251478 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.4	L;.;.
PhyloP100		3.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.49	N;N;.
REVEL	Benign	0.20
Sift	Benign	0.23	T;T;.
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.086
MutPred		0.14		Loss of phosphorylation at T637 (P = 0.0352);.;.;
MVP		0.40
MPC		0.68
ClinPred		0.13	T
GERP RS		3.0
Varity_R		0.071
gMVP		0.28
Mutation Taster		=58/42	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: rs1479706198; hg19: chr3-27758712; COSMIC: COSV105155409; COSMIC: COSV105155409;