Genetic Variant EOMES:p.Ala119_Ala120insGlyThr (chr3-27721936-G-GCGGTGC) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_001278182.2(EOMES):c.358_359insGCACCG(p.Ala119_Ala120insGlyThr) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000824 in 1,213,122 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A120A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

EOMES
NM_001278182.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.62

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_001278182.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EOMES	NM_001278182.2 link	c.358_359insGCACCG	p.Ala119_Ala120insGlyThr	conservative_inframe_insertion	Exon 1 of 6	ENST00000449599.4	NP_001265111.1	O95936-4B7Z4K0
EOMES	NM_005442.4 link	c.358_359insGCACCG	p.Ala119_Ala120insGlyThr	conservative_inframe_insertion	Exon 1 of 6		NP_005433.2	O95936-1B7Z4K0
EOMES	XM_005265510.5 link	c.358_359insGCACCG	p.Ala119_Ala120insGlyThr	conservative_inframe_insertion	Exon 1 of 7		XP_005265567.1
EOMES	NM_001278183.2 link	c.-5+493_-5+494insGCACCG		intron_variant	Intron 1 of 5		NP_001265112.1	O95936-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EOMES	ENST00000449599.4 link	c.358_359insGCACCG	p.Ala119_Ala120insGlyThr	conservative_inframe_insertion	Exon 1 of 6	1	NM_001278182.2	ENSP00000388620.1	O95936-4
EOMES	ENST00000295743.8 link	c.358_359insGCACCG	p.Ala119_Ala120insGlyThr	conservative_inframe_insertion	Exon 1 of 6	1		ENSP00000295743.4	O95936-1
EOMES	ENST00000461503.2 link	c.-5+493_-5+494insGCACCG		intron_variant	Intron 1 of 5	2		ENSP00000487112.1	O95936-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.24e-7

AC:

AN:

1213122

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

591022

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23740

American (AMR)

AF:

0.00

AC:

AN:

9520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17262

East Asian (EAS)

AF:

0.00

AC:

AN:

26210

South Asian (SAS)

AF:

0.00

AC:

AN:

43446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3352

European-Non Finnish (NFE)

AF:

0.00000100

AC:

AN:

998342

Other (OTH)

AF:

0.00

AC:

AN:

49450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over