22-41382175-A-C

Variant names:

• chr22-41382175-A-C
• rs2037036379
• NM_003216.4:c.131A>C

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.131A>C	p.Glu44Ala	missense	Exon 1 of 4	NP_003207.1	Q10587-1
	TEF	NM_001145398.3		c.68-5176A>C		intron	N/A	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.131A>C	p.Glu44Ala	missense	Exon 1 of 4	ENSP00000266304.4	Q10587-1
	TEF	ENST00000958295.1		c.131A>C	p.Glu44Ala	missense	Exon 1 of 4	ENSP00000628354.1
	TEF	ENST00000406644.7	TSL:2	c.68-5176A>C		intron	N/A	ENSP00000385256.3	Q10587-2

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148198 Hom.: 0 Cov.: 32

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: 1 AN: 1082426 Hom.: 0 Cov.: 34 AF XY: 0.00000195 AC XY: 1 AN XY: 512268

African (AFR) AF: 0.00 AC: 0 AN: 22980

American (AMR) AF: 0.00 AC: 0 AN: 9592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14002

East Asian (EAS) AF: 0.00 AC: 0 AN: 26636

South Asian (SAS) AF: 0.00 AC: 0 AN: 20088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3692

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 920892

Other (OTH) AF: 0.00 AC: 0 AN: 43486

GnomAD4 genome AF: 0.00000674 AC: 1 AN: 148298 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72338

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

African (AFR) AF: 0.00 AC: 0 AN: 39958

American (AMR) AF: 0.00 AC: 0 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.000209 AC: 1 AN: 4784

South Asian (SAS) AF: 0.00 AC: 0 AN: 4578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10048

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67196

Other (OTH) AF: 0.00 AC: 0 AN: 2096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

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	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.16
MutPred		0.39		Loss of ubiquitination at K41 (P = 0.0236)
MVP		0.60
MPC		1.9
ClinPred		0.98	D
GERP RS		4.4
PromoterAI		0.043	Neutral
Varity_R		0.45
gMVP		0.34
Mutation Taster		=59/41	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

dbSNP: rs2037036379; hg19: chr22-41778179;