3-27721936-G-GCGGCGC

Position:

• chr3-27721936-G-GCGGCGC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BA1

The NM_001278182.2(EOMES):​c.358_359insGCGCCG​(p.Ala119_Ala120insGlyAla) variant causes a 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 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.62

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 210936.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• 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/exons	MANE	UniProt
EOMES	NM_001278182.2	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	inframe_insertion	1/6	ENST00000449599.4
EOMES	NM_005442.4	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	inframe_insertion	1/6
EOMES	XM_005265510.5	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	inframe_insertion	1/7
EOMES	NM_001278183.2	c.-5+493_-5+494insGCGCCG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EOMES	ENST00000449599.4	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	inframe_insertion	1/6	1	NM_001278182.2	A1
EOMES	ENST00000295743.8	c.358_359insGCGCCG	p.Ala119_Ala120insGlyAla	inframe_insertion	1/6	1		P4
EOMES	ENST00000461503.2	c.-5+493_-5+494insGCGCCG		intron_variant		2

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

GnomAD3 exomes AF: 0.293 AC: 7018 AN: 23932 Hom.: 1392 AF XY: 0.304 AC XY: 4316 AN XY: 14176

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 SAS exome AF: 0.453

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

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.520

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.732

Gnomad4 SAS exome AF: 0.519

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.401

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

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.565

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.814

Gnomad4 SAS AF: 0.680

Gnomad4 FIN AF: 0.374

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.428

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 04, 2014	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553745484; hg19: chr3-27763427;