NM_001278182.2:c.358_359insGCG

Variant names:

• chr3-27721936-G-GCGC
• rs1553745484
• NM_001278182.2:c.358_359insGCG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3 BP6_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
• Clinical Significance: Benign criteria provided, single submitter 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: 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	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6	ENST00000449599.4	NP_001265111.1
EOMES	NM_005442.4	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6		NP_005433.2
EOMES	XM_005265510.5	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 7		XP_005265567.1
EOMES	NM_001278183.2	c.-5+493_-5+494insGCG		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_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6	1	NM_001278182.2	ENSP00000388620.1
EOMES	ENST00000295743.8	c.358_359insGCG	p.Ala119_Ala120insGly	conservative_inframe_insertion	Exon 1 of 6	1		ENSP00000295743.4
EOMES	ENST00000461503.2	c.-5+493_-5+494insGCG		intron_variant	Intron 1 of 5	2		ENSP00000487112.1

Frequencies

GnomAD3 genomes AF: 0.0000927 AC: 14 AN: 150988 Hom.: 0 Cov.: 0

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: 82 AN: 23932 AF XY: 0.00374

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.: 0 Cov.: 35 AF XY: 0.00126 AC XY: 720 AN XY: 569744

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

African (AFR) AF: 0.000258 AC: 6 AN: 23262

American (AMR) AF: 0.00116 AC: 10 AN: 8600

Ashkenazi Jewish (ASJ) AF: 0.000786 AC: 13 AN: 16530

East Asian (EAS) AF: 0.000925 AC: 20 AN: 21622

South Asian (SAS) AF: 0.0117 AC: 467 AN: 39890

European-Finnish (FIN) AF: 0.00168 AC: 68 AN: 40498

Middle Eastern (MID) AF: 0.00221 AC: 7 AN: 3162

European-Non Finnish (NFE) AF: 0.000543 AC: 527 AN: 969834

Other (OTH) AF: 0.00108 AC: 51 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.

GnomAD4 genome AF: 0.0000927 AC: 14 AN: 151098 Hom.: 0 Cov.: 0 AF XY: 0.0000678 AC XY: 5 AN XY: 73778

African (AFR) AF: 0.0000242 AC: 1 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15172

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4972

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.0000959 AC: 1 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67654

Other (OTH) AF: 0.000477 AC: 1 AN: 2096

Alfa AF: 0.00 Hom.: 310

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

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: COSV106057466;