Genetic Variant EOMES:p.Ala119_Ala120insGly (chr3-27721936-G-GCGC) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3BP6_Moderate

The NM_001278182.2(EOMES):c.358_359insGCG(p.Ala119_Ala120insGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A120A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EOMES
NM_001278182.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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: Likely_benign. The variant received -3 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001278182.2

BP6

Variant 3-27721936-G-GCGC is Benign according to our data. Variant chr3-27721936-G-GCGC is described in ClinVar as Benign. ClinVar VariationId is 771348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EOMES	NM_001278182.2 link	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6	ENST00000449599.4	NP_001265111.1	O95936-4B7Z4K0
EOMES	NM_005442.4 link	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6		NP_005433.2	O95936-1B7Z4K0
EOMES	XM_005265510.5 link	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 7		XP_005265567.1
EOMES	NM_001278183.2 link	c.-5+493_-5+494insGCG		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_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6	1	NM_001278182.2	ENSP00000388620.1	O95936-4
EOMES	ENST00000295743.8 link	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6	1		ENSP00000295743.4	O95936-1
EOMES	ENST00000461503.2 link	c.-5+493_-5+494insGCG		intron_variant	Intron 1 of 5	2		ENSP00000487112.1	O95936-3

Frequencies

GnomAD3 genomes

AF:

0.0000927

AC:

AN:

150988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.0000959

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000163

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.00343

AC:

AN:

23932

AF XY:

0.00374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00573

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00165

Gnomad NFE exome

AF:

0.00274

Gnomad OTH exome

AF:

0.00209

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000999

AC:

1169

AN:

1170716

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

720

AN XY:

569744

show subpopulations

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

African (AFR)

AF:

0.000258

AC:

AN:

23262

American (AMR)

AF:

0.00116

AC:

AN:

8600

Ashkenazi Jewish (ASJ)

AF:

0.000786

AC:

AN:

16530

East Asian (EAS)

AF:

0.000925

AC:

AN:

21622

South Asian (SAS)

AF:

0.0117

AC:

467

AN:

39890

European-Finnish (FIN)

AF:

0.00168

AC:

AN:

40498

Middle Eastern (MID)

AF:

0.00221

AC:

AN:

3162

European-Non Finnish (NFE)

AF:

0.000543

AC:

527

AN:

969834

Other (OTH)

AF:

0.00108

AC:

AN:

47318

⚠️ 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: 0.283

Heterozygous variant carriers

125

250

375

500

625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000927

AC:

AN:

151098

Hom.:

Cov.:

AF XY:

0.0000678

AC XY:

AN XY:

73778

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41328

American (AMR)

AF:

0.00

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4972

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0000959

AC:

AN:

10424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

67654

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

310

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=86/14

polymorphism

(source)

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over