chr10-129837933-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The ENST00000368648.8(EBF3):​c.1652T>C​(p.Met551Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

EBF3
ENST00000368648.8 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25
Variant links:
Genes affected
EBF3 (HGNC:19087): (EBF transcription factor 3) This gene encodes a member of the early B-cell factor (EBF) family of DNA binding transcription factors. EBF proteins are involved in B-cell differentiation, bone development and neurogenesis, and may also function as tumor suppressors. The encoded protein inhibits cell survival through the regulation of genes involved in cell cycle arrest and apoptosis, and aberrant methylation or deletion of this gene may play a role in multiple malignancies including glioblastoma multiforme and gastric carcinoma. [provided by RefSeq, Sep 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EBF3. . Gene score misZ 3.6113 (greater than the threshold 3.09). Trascript score misZ 3.1106 (greater than threshold 3.09). GenCC has associacion of gene with hypotonia, ataxia, and delayed development syndrome.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EBF3NM_001375380.1 linkuse as main transcriptc.*10T>C 3_prime_UTR_variant 17/17 ENST00000440978.2 NP_001362309.1
LOC107984281XR_001747650.2 linkuse as main transcriptn.6369-514A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EBF3ENST00000368648.8 linkuse as main transcriptc.1652T>C p.Met551Thr missense_variant 17/171 ENSP00000357637 A1Q9H4W6-2
EBF3ENST00000440978.2 linkuse as main transcriptc.*10T>C 3_prime_UTR_variant 17/173 NM_001375380.1 ENSP00000387543
EBF3ENST00000355311.10 linkuse as main transcriptc.1787T>C p.Met596Thr missense_variant 16/165 ENSP00000347463 P4Q9H4W6-1
EBF3ENST00000675373.1 linkuse as main transcriptn.1542T>C non_coding_transcript_exon_variant 14/14

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 13, 2022Variant summary: EBF3 c.1652T>C (p.Met551Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251414 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1652T>C in individuals affected with Hypotonia, Ataxia, And Delayed Development Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.14
.;T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.0062
T
MetaRNN
Uncertain
0.57
D;D
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
1.5
.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.29
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.53
P;.
Vest4
0.74
MutPred
0.43
Gain of glycosylation at M551 (P = 0.0042);.;
MVP
0.73
MPC
1.7
ClinPred
0.87
D
GERP RS
6.1
Varity_R
0.68
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-131636197; API