NM_001278182.2:c.358_359insGCTCCG

Variant names:

• chr3-27721936-G-GCGGAGC
• rs1553745484
• NM_001278182.2:c.358_359insGCTCCG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001278182.2(EOMES):​c.358_359insGCTCCG​(p.Ala119_Ala120insGlySer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,364,148 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: 𝑓 0.0000066 (0 hom., cov: 0)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: EOMES NM_001278182.2 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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: 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278182.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EOMES	NM_001278182.2	MANE Select	c.358_359insGCTCCG	p.Ala119_Ala120insGlySer	conservative_inframe_insertion	Exon 1 of 6	NP_001265111.1
	EOMES	NM_005442.4		c.358_359insGCTCCG	p.Ala119_Ala120insGlySer	conservative_inframe_insertion	Exon 1 of 6	NP_005433.2
	EOMES	NM_001278183.2		c.-5+493_-5+494insGCTCCG		intron	N/A	NP_001265112.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EOMES	ENST00000449599.4	TSL:1 MANE Select	c.358_359insGCTCCG	p.Ala119_Ala120insGlySer	conservative_inframe_insertion	Exon 1 of 6	ENSP00000388620.1
	EOMES	ENST00000295743.8	TSL:1	c.358_359insGCTCCG	p.Ala119_Ala120insGlySer	conservative_inframe_insertion	Exon 1 of 6	ENSP00000295743.4
	EOMES	ENST00000461503.2	TSL:2	c.-5+493_-5+494insGCTCCG		intron	N/A	ENSP00000487112.1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151026 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.24e-7 AC: 1 AN: 1213122 Hom.: 0 Cov.: 35 AF XY: 0.00000169 AC XY: 1 AN XY: 591022

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

African (AFR) AF: 0.00 AC: 0 AN: 23740

American (AMR) AF: 0.00 AC: 0 AN: 9520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17262

East Asian (EAS) AF: 0.00 AC: 0 AN: 26210

South Asian (SAS) AF: 0.0000230 AC: 1 AN: 43446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3352

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 998342

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151026 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73682

African (AFR) AF: 0.00 AC: 0 AN: 41210

American (AMR) AF: 0.0000660 AC: 1 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4990

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67684

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 310

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=86/14	polymorphism

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;