chr3-27721936-G-GCGGCGC

Variant names:

• chr3-27721936-G-GCGGCGC
• rs1553745484
• NM_001278182.2:c.358_359insGCGCCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BA1

The NM_001278182.2(EOMES):​c.358_359insGCGCCG​(p.Ala119_Ala120insGlyAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,353,548 control chromosomes in the GnomAD database, including 90,850 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A120A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13972 hom., cov: 0)
  • Exomes 𝑓: 0.38 (76878 hom.)
• Consequence: EOMES NM_001278182.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.62
• 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: Benign. The variant received -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001278182.2
• BP6: Variant 3-27721936-G-GCGGCGC is Benign according to our data. Variant chr3-27721936-G-GCGGCGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210936.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EOMES	NM_001278182.2	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	conservative_inframe_insertion	Exon 1 of 6	ENST00000449599.4	NP_001265111.1
EOMES	NM_005442.4	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	conservative_inframe_insertion	Exon 1 of 6		NP_005433.2
EOMES	XM_005265510.5	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	conservative_inframe_insertion	Exon 1 of 7		XP_005265567.1
EOMES	NM_001278183.2	c.-5+493_-5+494insGCGCCG		intron_variant	Intron 1 of 5		NP_001265112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EOMES	ENST00000449599.4	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	conservative_inframe_insertion	Exon 1 of 6	1	NM_001278182.2	ENSP00000388620.1
EOMES	ENST00000295743.8	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	conservative_inframe_insertion	Exon 1 of 6	1		ENSP00000295743.4
EOMES	ENST00000461503.2	c.-5+493_-5+494insGCGCCG		intron_variant	Intron 1 of 5	2		ENSP00000487112.1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62248 AN: 150912 Hom.: 13961 Cov.: 0

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.816

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.477

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.293 AC: 7018 AN: 23932 AF XY: 0.304

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.391

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.377 AC: 452917 AN: 1202526 Hom.: 76878 Cov.: 35 AF XY: 0.378 AC XY: 221472 AN XY: 585252

African (AFR) AF: 0.295 AC: 6979 AN: 23686

American (AMR) AF: 0.520 AC: 4917 AN: 9456

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 6733 AN: 17012

East Asian (EAS) AF: 0.732 AC: 19135 AN: 26138

South Asian (SAS) AF: 0.519 AC: 21379 AN: 41212

European-Finnish (FIN) AF: 0.338 AC: 13876 AN: 41076

Middle Eastern (MID) AF: 0.478 AC: 1586 AN: 3318

European-Non Finnish (NFE) AF: 0.362 AC: 358707 AN: 991712

Other (OTH) AF: 0.401 AC: 19605 AN: 48916

GnomAD4 genome AF: 0.412 AC: 62288 AN: 151022 Hom.: 13972 Cov.: 0 AF XY: 0.420 AC XY: 30986 AN XY: 73736

African (AFR) AF: 0.318 AC: 13123 AN: 41298

American (AMR) AF: 0.565 AC: 8576 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1570 AN: 3456

East Asian (EAS) AF: 0.814 AC: 4050 AN: 4974

South Asian (SAS) AF: 0.680 AC: 3264 AN: 4798

European-Finnish (FIN) AF: 0.374 AC: 3895 AN: 10402

Middle Eastern (MID) AF: 0.465 AC: 133 AN: 286

European-Non Finnish (NFE) AF: 0.392 AC: 26510 AN: 67638

Other (OTH) AF: 0.428 AC: 898 AN: 2096

Alfa AF: 0.185 Hom.: 310

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

May 17, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

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		=85/15	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553745484; hg19: chr3-27763427; COSMIC: COSV55411504;