22-41387609-C-A

Variant names:

• chr22-41387609-C-A
• NM_003216.4:c.416C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003216.4(TEF):​c.416C>A​(p.Ala139Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TEF NM_003216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16029263).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003216.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEF	NM_003216.4	MANE Select	c.416C>A	p.Ala139Glu	missense	Exon 2 of 4	NP_003207.1	Q10587-1
	TEF	NM_001145398.3		c.326C>A	p.Ala109Glu	missense	Exon 2 of 4	NP_001138870.1	Q10587-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEF	ENST00000266304.9	TSL:1 MANE Select	c.416C>A	p.Ala139Glu	missense	Exon 2 of 4	ENSP00000266304.4	Q10587-1
	TEF	ENST00000958295.1		c.431C>A	p.Ala144Glu	missense	Exon 2 of 4	ENSP00000628354.1
	TEF	ENST00000406644.7	TSL:2	c.326C>A	p.Ala109Glu	missense	Exon 2 of 4	ENSP00000385256.3	Q10587-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.0085
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.056
Sift	Benign	0.15	T
Sift4G	Benign	0.63	T
Polyphen		0.90	P
Vest4		0.31
MutPred		0.14		Gain of solvent accessibility (P = 0.08)
MVP		0.12
MPC		1.2
ClinPred		0.50	D
GERP RS		4.3
Varity_R		0.16
gMVP		0.62
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

hg19: chr22-41783613;