22-41382139-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_003216.4(TEF):​c.95C>T​(p.Ser32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,236,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TEF
NM_003216.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.35

Publications

0 publications found
Variant links:
Genes affected
TEF (HGNC:11722): (TEF transcription factor, PAR bZIP family member) This gene encodes a member of the PAR (proline and acidic amino acid-rich) subfamily of basic region/leucine zipper (bZIP) transcription factors. It is expressed in a broad range of cells and tissues in adult animals, however, during embryonic development, TEF expression appears to be restricted to the developing anterior pituitary gland, coincident with the appearance of thyroid-stimulating hormone, beta (TSHB). Indeed, TEF can bind to, and transactivate the TSHB promoter. It shows homology (in the functional domains) with other members of the PAR-bZIP subfamily of transcription factors, which include albumin D box-binding protein (DBP), human hepatic leukemia factor (HLF) and chicken vitellogenin gene-binding protein (VBP); VBP is considered the chicken homologue of TEF. Different members of the subfamily can readily form heterodimers, and share DNA-binding, and transcriptional regulatory properties. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity TEF_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15860415).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TEFNM_003216.4 linkc.95C>T p.Ser32Leu missense_variant Exon 1 of 4 ENST00000266304.9 NP_003207.1 Q10587-1
TEFNM_001145398.3 linkc.68-5212C>T intron_variant Intron 1 of 3 NP_001138870.1 Q10587-2
LOC105373042XR_938271.3 linkn.-228G>A upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TEFENST00000266304.9 linkc.95C>T p.Ser32Leu missense_variant Exon 1 of 4 1 NM_003216.4 ENSP00000266304.4 Q10587-1
TEFENST00000406644.7 linkc.68-5212C>T intron_variant Intron 1 of 3 2 ENSP00000385256.3 Q10587-2

Frequencies

GnomAD3 genomes
AF:
0.00000661
AC:
1
AN:
151172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000111
AC:
12
AN:
1084988
Hom.:
0
Cov.:
33
AF XY:
0.00000975
AC XY:
5
AN XY:
513026
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
23156
American (AMR)
AF:
0.00
AC:
0
AN:
9194
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
14318
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26748
South Asian (SAS)
AF:
0.00
AC:
0
AN:
19886
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
21226
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3818
European-Non Finnish (NFE)
AF:
0.0000119
AC:
11
AN:
922786
Other (OTH)
AF:
0.0000228
AC:
1
AN:
43856
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000661
AC:
1
AN:
151172
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
73856
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41200
American (AMR)
AF:
0.00
AC:
0
AN:
15198
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3462
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5052
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4728
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10460
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
0.0000148
AC:
1
AN:
67772
Other (OTH)
AF:
0.00
AC:
0
AN:
2082
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 18, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.95C>T (p.S32L) alteration is located in exon 1 (coding exon 1) of the TEF gene. This alteration results from a C to T substitution at nucleotide position 95, causing the serine (S) at amino acid position 32 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.0082
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T
Eigen
Benign
-0.11
Eigen_PC
Benign
0.041
FATHMM_MKL
Benign
0.76
D
LIST_S2
Benign
0.71
T
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L
PhyloP100
1.4
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.56
N
REVEL
Benign
0.071
Sift
Benign
0.074
T
Sift4G
Benign
0.31
T
Polyphen
0.41
B
Vest4
0.20
MutPred
0.27
Loss of phosphorylation at S32 (P = 0.0136);
MVP
0.18
MPC
0.93
ClinPred
0.87
D
GERP RS
4.4
PromoterAI
0.034
Neutral
Varity_R
0.18
gMVP
0.17
Mutation Taster
=77/23
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1246979495; hg19: chr22-41778143; API