22-41382175-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003216.4(TEF):c.131A>C(p.Glu44Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,230,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 9.2e-7 ( 0 hom. )

Consequence

TEF
NM_003216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.53

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]

TEF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEF	NM_003216.4 link	c.131A>C	p.Glu44Ala	missense_variant	Exon 1 of 4	ENST00000266304.9	NP_003207.1	Q10587-1
TEF	NM_001145398.3 link	c.68-5176A>C		intron_variant	Intron 1 of 3		NP_001138870.1	Q10587-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEF	ENST00000266304.9 link	c.131A>C	p.Glu44Ala	missense_variant	Exon 1 of 4	1	NM_003216.4	ENSP00000266304.4		Q10587-1
TEF	ENST00000406644.7 link	c.68-5176A>C		intron_variant	Intron 1 of 3	2		ENSP00000385256.3		Q10587-2

Frequencies

GnomAD3 genomes

AF:

0.00000675

AC:

AN:

148198

Hom.:

Cov.:

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:

0.000208

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:

9.24e-7

AC:

AN:

1082426

Hom.:

Cov.:

AF XY:

0.00000195

AC XY:

AN XY:

512268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22980

American (AMR)

AF:

0.00

AC:

AN:

9592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14002

East Asian (EAS)

AF:

0.00

AC:

AN:

26636

South Asian (SAS)

AF:

0.00

AC:

AN:

20088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3692

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

920892

Other (OTH)

AF:

0.00

AC:

AN:

43486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000674

AC:

AN:

148298

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72338

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

39958

American (AMR)

AF:

0.00

AC:

AN:

15002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.000209

AC:

AN:

4784

South Asian (SAS)

AF:

0.00

AC:

AN:

4578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67196

Other (OTH)

AF:

0.00

AC:

AN:

2096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.131A>C (p.E44A) alteration is located in exon 1 (coding exon 1) of the TEF gene. This alteration results from a A to C substitution at nucleotide position 131, causing the glutamic acid (E) at amino acid position 44 to be replaced by an alanine (A). 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

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-0.42

MutationAssessor

Benign

2.0

PhyloP100

2.5

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.21

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.027

Polyphen

0.99

Vest4

0.16

MutPred

0.39

Loss of ubiquitination at K41 (P = 0.0236);

MVP

0.60

MPC

1.9

ClinPred

0.98

GERP RS

4.4

PromoterAI

0.043

Neutral

(source)

Varity_R

0.45

gMVP

0.34

Mutation Taster

=59/41

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over